After winning another couple of fights, Thompson signed to face Dominick Guinn on March 18, 2006 in San Jose, California. Once described as "hot prospect" and viewed as one of the top-rising American heavyweight contenders, Guinn was looking to return to the heavyweight title contention after losses to James Toney, Siarhei Liakhovich and Monte Barrett. Many observers viewed Thompson fight as an opportunity for Guinn to follow up on his win over Audley Harrison. The fight was the main event of the card aired live on ESPN2 as part of the "Wednesday Night Fights" series. It was the first 12-round bout in Thompson's career. The first half of the fight was competitive, with Guinn aggressively coming forward, while Thompson fought behind the jab, landing cleaner punches. By the sixth round, Guinn started showing signs of fatigue. Thompson dominated the second half of the fight, patiently stalking tired Guinn and gradually accumulating the damage, hurting him on several occasions. Ultimately, Thompson was declared the winner by unanimous decision (UD), with scores 118–111, 119–109 and 117–111. Thompson's wife Sydnee later said that she had heard Guinn talking to his trainer, Joe Goossen, in the dressing room after the fight, with Guinn saying: "Thompson’s nothing like the videos we watched. This guy is good".