Five patients with chronic non-A, non-B hepatitis were entered into a pilot therapeutic study of the antiviral agent acyclovir [9-(2-hydroxyethoxymethyl) guanine]. Each patient received acyclovir by slow intravenous infusion in a dosage of 5 mg/kg every 8 hr for 10 days. During therapy, serum aminotransferase levels decreased by more than 50% in two patients, remained unchanged in two patients, and rose (by 32%) in the final patient. The two patients whose serum aminotransferase levels decreased during acyclovir treatment subsequently received a second course of drug using a higher dose (10 mg/kg every 8 hr for 10 days). Serum aminotransferase levels rose in both patients (by 54% and 121%) during the second course of therapy. Acyclovir was well tolerated in these patients, and there were no symptoms or signs attributable to drug toxicity during or after treatment. During a subsequent 12-month follow-up period, none of the five patients has manifested either a clinical or serum biochemical improvement in their chronic liver disease. Spontaneous fluctuations in serum aminotransferase levels unrelated to acyclovir therapy were noted in three of the five patients. These findings suggest that a short course of acyclovir does not have any appreciable long-term beneficial effect on the course of chronic non-A, non-B hepatitis.