On 8 July 2006, Maccarinelli fought against former World Boxing Council (WBC) cruiserweight champion Marcelo Fabian Domínguez for the WBO interim cruiserweight title. Maccarinelli won the title with a ninth-round TKO. The natural progression was a title fight against the then WBO title holder, Johnny Nelson. Due to several injuries to Nelson this matchup never transpired, and on 22 September 2006 he announced his retirement, automatically relinquishing the belt and allowing Maccarinelli to be promoted to full champion status.
On 14 October 2006 Maccarinelli made his first defence of the WBO title, stopping former opponent Mark Hobson in the first round in a fight that was widely expected to last the distance. This was followed by another first round win over Bobby Gunn on 7 April 2007 at the Millennium Stadium, Cardiff. The Gunn fight was stopped with just :25 seconds remaining in the first round by referee Mark Nelson, even though Gunn was not down and only had a small cut. It was widely and erroneously reported that Maccarinelli had broken Bobby Gunn's nose, but it was a small cut to the bridge of the nose that caused the bleeding. Gunn's nose was not broken and most observers at ringside thought the fight was stopped prematurely.
On 21 July 2007 Maccarinelli defended his WBO cruiserweight championship against former WBC champ Wayne Braithwaite and won by unanimous decision, after dominating the match. On 3 November 2007 Maccarinelli successfully defended his WBO cruiserweight title against Mohamed Azzaoui winning by TKO in the 4th Round.
Maccarinelli's next fight was an all-British unification fight against the WBA/WBC champion David Haye. The fight took place on 8 March 2008 at the O2 Arena, London and was much hyped in the weeks running up to the event, being given the tagline "bombs away" (referring to the high KO percentages and punching power both men boasted). Maccarinelli lost the fight and his WBO belt when he was knocked out in the 2nd round. A right hand by Haye knocked Maccarinelli down towards the end of the round and although he was able to get back up it was on unsteady legs and the referee stepped in to stop the fight.
After the fight Haye announced that he would be moving up to the heavyweight division with immediate effect and would therefore be vacating his newly won belts. Because of this Maccarinelli received an immediate opportunity to reclaim his WBO belt in a matchup against undefeated American Jonathon Banks for the now vacant championship, but due to injury Banks was forced to pull out. After several replacements were unable to fight, Maccarinelli instead stepped up to heavyweight to face Matthew Ellis. Maccarinelli won after a 2nd-round KO in what was his debut at the higher weight. After the fight Frank Warrenannounced that Maccarinelli would face Banks in a re-scheduled bout for the WBO belt during February 2009.
Once again the Banks fight proved to be a non-starter (Banks opted to make an ultimately unsuccessful attempt to win the IBF cruiserweight title against Tomasz Adamek) and instead Maccarinelli's next fight was against the American-based Londoner Ola Afolabi for the "interim" WBO title. The fight took place on 14 March at the M.E.N. Arena in Manchester, on the undercard of the Amir Khan vs Marco Antonio Barrera bout. Maccarinelli was favoured by most observers to win, however things did not go as expected as Maccarinelli struggled in the early rounds and was staggered in the 3rd round by a short chopping right hand from the slick Afolabi. Despite managing to recover and win the majority of the next few rounds he was knocked out by Afolabi in round 9 when a huge overhand right put him on the canvas and forced the referee to call off the fight.
Maccarinelli's next fight was against the unbeaten Russian Denis Lebedev on 18 July 2009. As with the Afolabi contest the fight took place at the M.E.N. Arena on the undercard of an Amir Khan fight, this time Khan's WBA light-welterweight title challenge against Andreas Kotelnik. From the very beginning of the fight Maccarinelli struggled with the power of his opponent and by the end of the second round his right eye had swollen completely shut from the punches landed by Lebedev. In the third round Lebedev rocked Maccarinelli with an uppercut which landed cleanly through his guard and after a further barrage of unanswered punches the referee stepped in and called a stop to the fight.
Before the fight Maccarinelli had admitted that the contest represented "the last chance saloon" in terms of getting his career back on track, following 2 KO losses in his last 3 fights, and talking immediately after the defeat he hinted that this latest setback could signal the end of his boxing career. In an interview with his local paper a few days later Maccarinelli apparently confirmed his intention to retire from the sport, although he retracted this in a later interview with the same source.
Maccarinelli began his latest comeback attempt on another Amir Khan undercard, this time Khan's WBA Light-Welterweight title defence against on 5 December at the Metro Radio Arena in Newcastle. His opponent was the relatively unknown Hungarian journeyman Krisztian Jaksi. who provided little resistance and was knocked out in the 1st round. Maccarinelli managed a second consecutive 1st-round KO victory against Hungarian opposition when he defeated Zoltan Czekus at the Echo Arena Liverpool on 13 March 2010.
Following his two quick comeback wins Maccarinelli's next fight took place on 27 April 2010 when he fought Russian prospect Alexander Kotlobay in St Petersburg for the vacant European cruiserweight title. Despite now being the fighter that had to travel and fight on someone else's patch, Maccarinelli scored his third consecutive quick victory when he knocked Kotlobay down with an overhand right before the referee stepped in to end the fight at 2:15 of the first round.
His first defence of his newly won title came as part of Frank Warren's "Magnificent Seven" fight card, which took place on 18 September 2010 at the LG Arena in Birmingham. His opponent for this defence was the undefeated Ukrainian prospect Alexander Frenkel. Despite a tentative opening round Maccarinelli improved and managed to rock his opponent in the fourth round with a right hand. A clash of heads in the sixth led to a cut developing over his right eye, however the fight still appeared to be going Maccarinelli's way until he was knocked down heavily towards the end of round seven by a left hook from Frenkel. Despite managing to rise by the count of nine he was extremely unsteady and appeared to be in no position to defend himself. However the referee allowed the bout to continue, only for it to be stopped a few seconds later when a three punch combination from Frenkel led to a second knockdown. The final blows were struck with such ferocity that Maccarinelli was knocked unconscious and required oxygen and medical attention before being able to leave the ring. At the time of the fight there was heavy criticism from both journalists and fellow boxers at the decision by the referee to allow the fight to continue after the first knockdown, when it was clear that Maccarinelli was in no position to defend himself.
As with the aftermath of the Afolabi and Lebedev defeats there were also been calls for Maccarinelli to retire from the ring, something which the boxer himself admitted to the press was a distinct possibility following his fourth KO loss in eight fights.
After a period of inactivity following the Frenkel defeat, in February 2011 Maccarinelli announced that rather than retiring he would instead be dropping down in weight to compete in the 175 lb light-heavyweightdivision, with a view to having his first fight at the weight limit later on in the year.
Several months later he made the further announcement that he would once again be working with former coach Enzo Calzaghe, who was part of Maccarinelli's team during his successful run at cruiserweight. At the same time he also expressed a desire to fight for a world title at the new weight limit in the future, and in particular put forward the idea of an all Welsh title fight between himself and current WBO belt holder Nathan Cleverly.
Exactly 14 months after his last in-ring appearance Maccarinelli's first fight at the new weight limit took place at the York Hall in Bethnal Green on 18 November 2011. As with 2 of his previous 4 fights at cruiserweight the opponent was a Hungarian fighter, this time the undefeated (and relatively unknown) Gyorgy Marosi. Maccarinelli emerged victorious, scoring a 1st-round TKO victory after just 99 seconds against an overmatched Marosi.
Following the successful debut at 175 lbs Maccarinelli reiterated his desire to fight for a world title at 175 lbs and again made reference to an all Welsh bout with Cleverly, although ruled out the prospect of such a matchup occurring straight away.
In 2015 Maccarinelli returned to cruiserweight and in December knocked out the then 46-year-old Roy Jones Jr. in the fourth round at the VTB Ice Palace in Moscow. In June 2016 he fought Dmytro Kucher for the vacant European cruiserweight title, but lost by TKO in the first round, subsequently announcing his retirement from boxing.