Negotiations for a proposed match between Mayweather and The Ring #3 pound-for-pound Shane Mosley began right after Andre Berto pulled out of his scheduled January 30 unification bout with Mosley due to the 2010 Haiti earthquake. Both sides eventually agreed to fight on May 1, 2010, for Mosley's WBA super-welterweight title. It was later revealed that Mayweather refused to pay sanctioning fees required by the WBA, saying "All belts do is collect dust". However, the belt was only on the line for Mosley to defend against Mayweather. Both Mayweather and Mosley agreed to Olympic-style testing for this bout.
Both sides agreed to enter into mediation on January 7, 2010, in hopes of coming to an agreement on the blood testing issue. Retired federal judge Daniel Weinstein, who successfully resolved a prior dispute between Top Rank and Golden Boy Promotions, would again act as mediator. Two days later, after hours of negotiating during mediation, Arum declared that the fight was officially off after Mayweather refused to agree to a 24-day cut-off date. Mayweather revealed that he offered a 14-day cut-off date to Team Pacquiao, but it was rejected.
Mayweather Promotions CEO Leonard Ellerbe declared on January 18, 2010, that random blood and urine testing will be implemented in all of Mayweather's future fights, regardless of the opponent. On February 13, 2010, in an exclusive interview with David Mayo of The Grand Rapids Press, Mayweather said, "I gave him [Pacquiao] a chance, up to 14 days out. But my new terms are all the way up to the fight. They can come get us whenever, all the way up to the fight, random drug test. That's what it is."
After the failed negotiations, both fighters moved on to instead face other opponents. On March 13, 2010, Pacquiao defeated Joshua Clottey via unanimous decision, and on May 1, 2010, Mayweather beat Shane Mosley by a unanimous decision.
Pacquiao was quoted by the Manila Bulletin on May 20, 2010, as saying, "As long as they're not getting a large amount of blood, I am willing to give out blood as close to two weeks before the fight." On the same day, Mayweather revealed that he would be taking the rest of 2010, and possibly 2011, off.
On June 10, 2010, Oscar De La Hoya said negotiations for a Mayweather-Pacquiao fight were close to being finalized. Speaking to Spanish-language sport show República Deportiva, De La Hoya briefly talked about the current status of negotiations and, with a grin on his face, said that the two sides were extremely close to making the biggest fight in boxing a reality. "These negotiations have been real difficult for various reasons, but we're really close to finalizing the contracts, even though they've been complicated," he commented. "Today, I can't really talk about the negotiations, but we're really close." A week later, Golden Boy Promotions CEO Richard Schaefer refuted De La Hoya's comments. "I saw those quotes as well, and I had no idea what Oscar was talking about. And I called him up and asked him about them, and he said that he was misquoted," Schaefer explained to Lem Satterfield of FanHouse.
Arum declared on June 30, 2010, that there were no longer any issues and the decision was up to Mayweather. "That's all been resolved," Arum stated to Kevin Iole of Yahoo! Sports regarding the dispute over random blood and urine drug testing. Arum would also tell the Las Vegas Review-Journal, "There's no longer any issues....The question is whether Mayweather is willing to fight this year." He would reiterate that comment to the Manila Bulletin, stating, "It's now up to Mayweather if he wants to fight."
On July 13, 2010, Arum issued a July 16 midnight deadline for Mayweather. "Mayweather has until the end of the week. He could wait until the last minute. If it's Friday [July 16] and it's 11 p.m., and he says we have a deal, we have a deal," Arum would explain to Dan Rafael of ESPN. On July 15, 2010, Top Rank's website unveiled an official countdown to the deadline entitled "Money" Time: Mayweather's Decision.
On July 19, 2010, Ellerbe denied that negotiations ever took place and nothing was ever agreed on. Ellerbe stated:
On September 9, 2010, it was reported that Mayweather was being sought by police for questioning after his former girlfriend, Josie Harris, filed a domestic battery report against him. Harris accused Mayweather of battery in the past, but those charges were dropped in July 2005 after Harris testified that she had lied and that Mayweather had not battered her. Mayweather was taken into custody September 10, 2010, but was released after posting $3,000 bail. Mayweather was initially charged with felony theft (stemming from the disappearance of Harris's mobile phone); on September 16 two felony coercion charges, one felony robbery charge, one misdemeanor domestic-battery charge and three misdemeanor harassment charges were added.