A77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, was administered to asymptomatic HIV-1-infected patients in a phase I trial. The drug was given by continuous intravenous infusion at dosages of 0.035, 0.07, 0.14, and 0.28 mg/kg of body weight per h. The drug was given first for 24 h and then for up to an additional 4 weeks in a second infusion period following at least a 6-day washout. Apart from reversible increases in hepatic transaminase levels in some patients, no systemic toxicities occurred during extended infusion of the drug. Dose-related local vein irritation, despite dilution of the infusate, however, caused severe infusion site phlebitis precluding dosage escalation beyond 0.28 mg/kg/h. Pharmacokinetic analysis demonstrated dose linear increases in mean steady-state concentrations. However, clearance of the drug from plasma was unexpectedly high, avenging 62 liters/h across all groups. The concentrations of A77003 in plasma achieved the in vitro 50% inhibitory concentration (0.16 μg/ml) only in the 0.28-mg/kg/h dosage group, but it did not attain the 90% inhibitory concentration (0.48 μg/ml). No statistically significant effect on CD4 cell numbers occurred in any of the groups, and there was no evidence of antiviral activity, as determined by HIV-1 p24 antigen level, quantitative plasma and cell culture, and quantitation of viral RNA in plasma. In conclusion, A77003, as formulated in the present study, causes severe phlebitis, which prevents administration of the infusates necessary to achieve high concentrations of the drug in plasma. The lack of antiviral activity observed in the study may be a consequence of the low concentrations in plasma in all groups.