We conducted a retrospective chart review to estimate the potential for drug interactions in subjects infected with the human immunodeficiency virus-1 when a protease inhibitor was added to existing therapy. Medical records of 50 patients in each of three immunologic strata (CD4 cell counts/microl < 100, 100-199, 200-500) were randomly selected from records of all patients receiving care at the clinic; 114 records were evaluable. The probabilities of one interaction or more were 31%, 42%, and 77% of patients if treated with indinavir, saquinavir, and ritonavir, respectively, across all CD4 groups; when the CD4 count was below 100 cells/microl, the probabilities were 55%, 63%, and 93%. Many of these interactions, however, resulted from administration of rifabutin, a drug likely to decrease in importance as less toxic alternatives become more widely administered. The potential for drug interactions is high when starting protease inhibitor therapy, especially in patients with low CD4 cell counts who receive ritonavir. Concurrent therapy must be evaluated before treatment, as many agents are either contraindicated or require dosage modification.