[15] In his first major competition of 2002, Peirsol won five medals (three gold, one silver, one bronze) at the 2002 FINA World Swimming Championships (25 m) in Moscow.

[16][17][18][19][20] At the 2002 Pan Pacific Swimming Championships in Yokohama, Japan, Peirsol won gold in the 100 and 200-meter backstroke and the 4×100-meter medley relay.

[21] At the 2003 World Aquatics Championships in Barcelona, Spain, Peirsol won gold in the 100 and 200-meter backstroke and the 4×100-meter medley relay.

[22] Peirsol participated in the 4×200-meter freestyle relay with Michael Phelps, Nate Dusing, and Klete Keller to win silver behind Australia.

[23] Peirsol then competed in the 200-meter backstroke and won gold in a time of 1:55.92, almost two seconds ahead of second-place finisher Gordan Kožulj of Croatia.

[26] In his last event, Peirsol competed in the 4×100-meter medley relay with Brendan Hansen, Ian Crocker, and Jason Lezak.

Four years after finishing in 4th place at the 2000 U.S. Olympic Team Trials, Peirsol won the 100-meter backstroke title, beating Lenny Krayzelburg.

In his first event, the 100-meter backstroke, Peirsol won gold in a time of 54.06, 0.29 s ahead of second-place finisher Markus Rogan of Austria.

[35] In his last event, the 4×100-meter medley relay, Peirsol combined with Brendan Hansen, Ian Crocker, and Jason Lezak to win gold in a world record time of 3:30.68, 2.94 s ahead of second-place finisher Germany.

[37] Peirsol caused minor controversy when he accused Kosuke Kitajima of Japan of using an illegal dolphin kick in the 100-meter breaststroke final when compatriot Brendan Hansen lost by 0.17 s.[38] Shortly after the 2004 Summer Olympics, Peirsol competed at the 2004 FINA World Swimming Championships (25 m) in Indianapolis where he won three gold medals.

In the 200-meter backstroke, Peirsol won gold in a world record time of 1:50.52, bettering his old mark of 1:50.64 (set earlier in 2004) and finished 2.02 s ahead of Matt Welsh of Australia.

[40][41] Peirsol then competed in the 4×100-meter medley relay with Brendan Hansen, Ian Crocker, and Jason Lezak to win gold in a world record time of 3:25.09, 4.63 s ahead of Australia.

[46] At the 2005 World Aquatics Championships in Montreal, Quebec, Peirsol won gold in the 100 and 200-meter backstroke and the 4×100-meter medley relay.

In his first event, the 100-meter backstroke, Peirsol won gold in a time of 53.62, just 0.01 s off his championship record set two years earlier in Barcelona.

[48] Peirsol then competed in the 4×100-meter medley relay with Brendan Hansen, Ian Crocker, and Jason Lezak to win gold in a time of 3:31.85, 3.23 s ahead of second-place finisher Russia.

[51][52] At the 2006 Pan Pacific Swimming Championships in Victoria, British Columbia, Peirsol won gold in the 100 and 200-meter backstroke and the 4×100-meter medley relay.

In his first event, the 100-meter backstroke, Peirsol won ahead of Matt Grevers with a world record time of 52.89, lowering his previous mark of 52.98 set last year.

[65][66] In his second event, the 200-meter backstroke, Peirsol won in a time of 1:54.32, equalling Ryan Lochte's world record set last year.

In his first event, the 100-meter backstroke, Peirsol was the heavy favorite for gold, with him being the world-record holder and the defending Olympic champion.

[70] In his last event, the 4×100-meter medley relay, Peirsol combined with Brendan Hansen, Michael Phelps, and Jason Lezak to win gold in a world record time of 3:29.34, lowering the old mark of 3:30.68 set four years ago in Athens.

In his first event, the 100-meter backstroke, Peirsol surprised many after he failed to make the final, which he attributed to a miscalculation of his own position in the semi-finals.

[80] In his last event, the 4×100-meter medley relay, Peirsol combined with Eric Shanteau, Michael Phelps, and David Walters to win gold in a world record time of 3:27.28, lowering the old mark of 3:29.34 set a year ago in Beijing.

[81] While leading off the relay, Peirsol broke the championship record in the 100-meter backstroke with a time of 52.19, bettering the previous mark of 52.26 set by Junya Koga.

[87] At the 2010 Pan Pacific Swimming Championships in Irvine, California, Peirsol won gold in the 100-meter backstroke and the 4×100-meter medley relay.

[89] Peirsol then competed in the 200-meter backstroke but did not qualify to swim in the medal-awarding final, with Lochte and Tyler Clary taking the top two American spots.

[90] In his final event, the 4×100-meter medley relay, Peirsol won gold along with compatriots Mark Gangloff, Michael Phelps, and Nathan Adrian.

Peirsol said it was "poetic" that 2010 Pan Pacific Swimming Championships, his final competition, was held at the pool where he trained in childhood.

[95][96] In November 2015 it was announced that Peirsol would be inducted into the International Swimming Hall of Fame Class of 2016 alongside fellow Americans Dara Torres and coach Bob Bowman.