After fighting just twice since 2007, Mayweather announced Tuesday his plans to challenge WBC welterweight champion Victor Ortiz on Sept. 17.
Mayweather, 34, revealed the news via Twitter, where he has more than 1.25 million followers.
"My fans have been waiting long enough," Mayweather tweeted. "Floyd Mayweather vs Victor Ortiz. Sept-17 2011 for the WBC World Championship."
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The Mayweather-Ortiz fight has been rumored for weeks -- even briefly appearing as an official entry on the BoxRec.com listings site for Cowboys Stadium in Arlington, Texas -- though both camps continued to deny the negotiations.
No venue for the fight has been announced. The likely location is Las Vegas -- Mayweather's home and the site of his last six bouts -- though Cowboys Stadium is reportedly still an option.
Mayweather (41-0, 25 KOs) has held world titles at super featherweight, lightweight, light welterweight, welterweight and super welterweight. His last fight was a victory by unanimous decision over Shane Mosley on May 1, 2010.
A longtime fixture atop various pound-for-pound lists, Mayweather was dropped from most organizations' rankings (including SI.com's) last month because of inactivity.
The 24-year-old Ortiz (29-2-2, 22 KOs), who recently moved up from junior welterweight, won the WBC's 147-pound title from Andre Berto in an impressive 12-round decision in April on HBO. The back-and-forth fight included four knockdowns and is widely regarded as a Fight of the Year candidate.
Mayweather sat ringside for the Ortiz-Berto fight at the Foxwoods Resort in Mashantucket, Conn.
"At this stage of my career, these are the challenges I look for, a young, strong, rising star looking to make his mark in boxing by beating me," Mayweather said in a subsequent release. "Like the rest of my opponents, he is going to try to prove that he can beat me. I commend him for accepting the fight, but on September 17, Ortiz is just going to be another casualty, the 42nd one who tried and failed. Trust me, I will be ready."
Manny Pacquiao, current pound-for-pound kingpin and Mayweather's primary rival, is tentatively scheduled to defend his WBO welterweight title against Juan Manuel Marquez on Nov. 12 in Las Vegas.
That would put Mayweather and Pacquiao on schedule for a potential May 2012 meeting, provided they can resolve their long-simmering differences over money and drug-testing.
Mayweather's time away from the ring has been riddled with legal troubles. He faces felony charges in a domestic argument with his ex-girlfriend and two of their children last year.
And he faces misdemeanor harassment charges accusing him of threatening two homeowner association security guards outside his Las Vegas home. The charges stem from an October dispute over parking with guards in the gated community where the prizefighter lives.
Mayweather also faces a September trial on a misdemeanor battery charge stemming from allegations he poked a 21-year-old guard in the face during a separate argument over parking tickets in November.