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Costs of medications for ambulatory HIV-infected people increase as knowledge of antiretroviral therapy and therapy for opportunistic infection grows. We evaluated the evolution of drug costs for HIV-infected persons who attend a university clinic in Baltimore, Maryland. Cross-sectional abstracts of a cohort of patients for four periods, corresponding to landmark changes in therapy, who attended the clinic between June 1995 and September 1996 were obtained. Monthly medication costs for all patients were calculated. Mean costs increased significantly (p < .01) from period 1 ($447 U.S.) to period 4 ($1048 U.S.). Multivariate analysis only revealed higher costs for patients with a CD4+ count <200 cells/mm3 (p < .001). The proportion of costs attributable to antiretroviral therapy increased from 34% in period 1 to 53% in period 4. Combination therapy increased >10-fold, from 8% in period 1 to 94% in period 4. Protease inhibitor use also increased significantly, from 4% in period 2 to 53% in period 4. We quantified the increase in costs of medications from mid-1995 to late 1996. Increases in costs appear to be the result of increasing complexity of drug regimens, particularly antiretroviral therapy in combinations.