Cameron connected in his first four at-bats for the Seattle Mariners at Chicago. He did it in just five innings, almost assuring him at least another at-bat.
Mark Whiten was the last player to homer four times in a game, doing it on Sept. 7, 1993, for St. Louis in the second game of a doubleheader. Rocky Colavito was the last to do it in the AL, on June 10, 1959, for Cleveland.
Cameron began his historic night by joining with Bret Boone to become the first teammates ever to both hit two home runs in the same inning. They connected back-to-back twice in a 10-run first against Chicago.
Cameron hit a solo shot in the third inning, and added another solo homer with two outs in the fifth.
After hitting his fourth homer to make it 13-1, Cameron rounded the bases with a big grin on his face. He slapped hands with third-base coach Dave Myers and got a big hug from teammate Ruben Sierra after he crossed home plate.
With the crowd at Comiskey Park giving him a standing ovation, Cameron headed to the dugout as the rest of the Mariners came out to greet him.
Cameron began the night with five home runs in 91 at-bats. Until this game, the 2001 All-Star and Gold Glove winner was known more his spectacular catches in center field than his hitting.
Cameron, 29, started his major league career with the White Sox in 1995 and joined Cincinnati in 1999. After one season with the Reds, he was traded to Seattle as part of the deal for Ken Griffey Jr.
Last year, Cameron hit a career-high 25 home runs. He had never hit more than two homers in a game until Thursday night.
Cameron's first home run of the night came against Jon Rauch, a drive on a 1-2 pitch to center. He connected again in the first inning off reliever Jim Parque, a full-count shot to center.
In the third, Cameron hit an 0-1 pitch from Parque over the left-field fence. He homered again off Parque in the fifth, launching a 2-1 pitch to center.
Cameron, Boone and the Mariners made history right from the start.
After Ichiro Suzuki was hit by a pitch leading off the game, Boone and Cameron homered. Two outs later, Boone and Cameron did it again.
There had only been 39 previous occasions of a player hitting two home runs in an inning, according to the Elias Sports Bureau. Eric Karros was last to do it, on Aug. 22, 2000, for Los Angeles. Mark McGwire was the previous AL player to do it, on Sept. 22, 1996, for Oakland.
Boone and Cameron became the first Mariners to homer twice in an inning.
Hoping to generate more runs after losing three straight, Mariners manager Lou Piniella shuffled his lineup for the game. Boone, who led the AL in RBIs last season, was bumped up to No. 2 in the order and Cameron was moved to No. 3.
It was the second time in team history the Mariners have hit four home runs in one inning. The first time was on Sept. 21, 1996, in the third inning against Oakland.
Alex Rodriguez had been the last Seattle player to homer three times in a game, doing it at Toronto on April 16, 2000.
Houston's Lance Berkman hit three homers on April 16 at Cincinnati.