Background: HIV-1 protease is required for virion maturation and infectivity. Ritonavir is a potent inhibitor of HIV-1 protease in vitro and has favorable oral bioavailability in humans. The goal of this study was to assess the safety and efficacy of this compounds in HIV-1-infected persons. Methods: Ritonavir was orally administered to 62 subjects at one of four doses in a 12 week trial with 4-week randomized, placebo-controlled, double-blinded phase followed by an 8-week dose-blinded phase. Antiviral response was assessed by serial plasma viremia measurements, and immunologic response was determined by serial CD4 cell counts. Results: Fifty two subjects completed the 12-week trial. Diarrhea and nausea were the most common side effects, while reversible elevations in serum triglyceride and gamma-glutamyl transferase were the most frequent laboratory abnormalities. The antiviral effect of ritonavir was rapid and prominent, with a mean maximal reduction in copies of HIV-1 RNA in plasma ranging from 0.86 to 1.18 log in the four dosing groups. After 12 weeks of treatment, the antiviral effect was partially maintained at a mean reduction in plasma viremia of 0.5 log. Using a more sensitive assay for HIV-1 RNA in plasma in a subset of 20 subjects, a mean reduction of 1.7 log in plasma viremia was documented; this antiviral effect was partially sustained with a mean reduction of approximately 1.1 log at week 12. In conjunction with the antiviral effect, CD4 lymphocyte counts rose following ritonavir administration, with median increases of 74 cells per microliter at week 4 and 99 cells per microliter at week 12. Conclusions: Ritonavir monotherapy is well tolerated and is associated with a potent antiviral effect that results in a substantial decrease in plasma viremia and a significant elevation of CD4 lymphocyte count. Expanded clinical trials of ritonavir are warranted.