The incidence of infection with Mycobacterium avium complex (MAC) is increasing among patients with AIDS. Although numerous antimicrobial regimens have been proposed as treatment for this infection, it is unclear which therapy is most effective. For this reason, we prospectively evaluated rifabutin (600 mg/d) vs. a placebo, each in combination with clofazimine and ethambutol, for the treatment of MAC bacteremia. Patients in the rifabutin group had a significantly higher rate of microbiological response (defined as either sterilization of the blood or at least a 2-log10 reduction in mycobacterial titers). By week 4 of therapy, 7 of 11 patients receiving rifabutin, vs. 0 of 13 in the placebo group, had responded (P < .001). Similar results were seen at later time points (7 of 10 vs. 1 of 8 responded to rifabutin by week 8, and 6 of 9 vs. 1 of 7 responded to a placebo by week 12). These results indicate that, in combination with other antimicrobial agents, rifabutin may be effective in the treatment of disseminated MAC infection.