In June 1993, the United States Public Health Service (USPHS) made recommendations for treatment of disseminated Mycobacterium avium complex (MAC) in patients infected with the human immunodeficiency syndrome (HIV). It was suggested that every treatment regimen include either azithromycin or clarithromycin plus one or more of the following drugs: ethambutol, clofazimine, rifabutin, rifampin, ciprofloxacin, or amikacin. This study compares the effect of multiple drug therapy regimens on the survival of patients of the HIV outpatient department of the Medical Center of New Orleans, Louisiana. A retrospective chart review of 122 confirmed cases of MAC was conducted. Three treatment groups were considered: no/monotreatment (n = 40), multitreatment without clarithromycin (n = 32), and multitreatment with clarithromycin (n = 50). Azithromycin, amikacin, and rifabutin were not used in this clinic during the study period. Both multitreatment without clarithromycin (p < 0.03) and multitreatment with clarithromycin (p < 0.005) were significantly protective for survival after adjusting for CD4 cell count at time of diagnosis, nonadherence to treatment, number of concomitant opportunistic infections at diagnosis, and weight loss > 10%. Neither of the groups that received multidrug therapy were significantly less likely to have MAC-related symptoms than the no/mono group at 3 and 6 months postdiagnosis. These findings support the USPHS recommendation for multiple drug treatment either with or without clarithromycin. Prospective controlled clinical trials will clarify the optimal regimen for disseminated MAC disease.