During a randomized study of clarithromycin plus clofazimine with or without ethambutol in patients with AIDS and Mycobacterium avium complex (MAC) bacteremia, eight participants received additional antimycobacterial drugs following the detection of a clarithromycin-resistant isolate (MIC, > 8 micrograms/mL). A macrolide (seven received clarithromycin, one azithromycin) and clofazimine were continued; additional treatment included various combinations of ethambutol, ciprofloxacin, amikacin, and rifabutin. After the detection of a resistant isolate and before receipt of additional antimycobacterials, the median peak MAC colony count in blood was 105 cfu/mL (range, 8-81,500 cfu/mL). After additional antimycobacterials, the median nadir MAC colony count was 5 cfu/mL (range, 0-110 cfu/mL). Five (63%) of eight patients had a > or = 1 log10 decrease, including two who achieved negative blood cultures; all of these responses occurred in patients originally assigned to clarithromycin plus clofazimine. Treatment of clarithromycin-resistant MAC bacteremia that emerges during clarithromycin-based treatment can decrease levels of bacteremia and transiently sterilize blood cultures.