We performed a phase 1–2 antiviral dose escalation trial of rifabutin, a rifamycin antibiotic with anti-HIV-1 activityin vitro.We followed 16 men with AIDS-related complex (ARC) for a mean duration of 29 weeks; the maximum toxicity-limited dose of rifabutin was 2400 mg/day, which was achieved in two patients. There was some evidence of anti-HIV-1 activity in two patients, one of whom had an improvement in immune status, but 11 of the 16 patients showed a deterioration in either virologic or immunologic status. The majority of the patients under study remained clinically stable during the trial, but there was clinical deterioration in the three who entered with CD4 cell counts of less than 100 x 106/l. On the basis of this trial, rifabutin as a single antiviral agent does not appear to be beneficial to ARC patients.