In a previous study a partial inhibition of viral replication was observed in HBeAg-positive patients after acyclovir (ACV) treatment. To assess those results and to evaluate different treatment regimens, a randomized controlled trial with ACV given at 45 mg/kg/day by continuous infusion (in 5 patients) or by intermittent 8-hourly infusion (in 6 patients) for 28 days versus placebo has been performed in 20 patients affected by chronic hepatitis positive for both HBsAg and HBeAg for at least 6 months. Patients were stratified for sex, presence of cirrhosis and homosexual activity. Modest inhibition of serum DNA polymerase activity was observed after intermittent ACV treatment but not with the continuous infusion. After a 8-12 months follow-up, 2 of 10 of the ACV-treated patients and 3 of the controls had become HBeAg-negative, with 1 and 2 seroconversions to anti-HBe in the treated and placebo group respectively. No adverse effects were observed in ACV-treated patients after continuous infusion, but 2 of 6 patients who received intermittent therapy had to stop treatment, because of abdominal colics and elevation of the serum creatinine. Our data confirm that ACV partially inhibits viral replication in HBeAg-positive patients but without significantly affecting the rate of seroconversion to anti-HBe.