High-level adherence to regimens of combination antiretroviral therapy and prophylactic medications for opportunistic infections (OIs) is crucial to their success. However, little is known about the association between adherence to these life-sustaining therapies and such clinical outcomes as progression of acquired immune deficiency syndrome (AIDS) or development of OIs. We assessed adherence to regimens of antiretroviral and Mycobacterium avium complex (MAC) prophylactic medications in 643 patients enrolled in a trial of MAC prophylaxis. By week 56 of the study follow-up, 42% of the patients reported nonadherence to MAC prophylaxis, whereas one-quarter of the patients reported nonadherence to potent antiretroviral regimens. Nonadherence to both MAC prophylaxis and antiretroviral therapy was associated with higher human immunodeficiency virus (HIV) type 1 RNA levels and a significant increase in the risk of developing an AIDS-defining complication or death. Predictors of nonadherence are presented. These results underscore the clinical significance of adherence to HIV therapy and may be helpful in designing interventions to optimize the management of HIV by improving adherence.