Fifty six previously untreated patients who had been positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) for more than 1 year with detectable serum levels of hepatitis B virus DNA (HBV-DNA) and a liver biopsy performed in the 6 months before enrollment, were randomized to receive recombinant alpha-2a interferon at doses of 3MU intramuscolarly thrice weekly for 6 months or no treatment. Treated and untreated patients had similar clinical characteristics in terms of ALT elevation, HBV-DNA levels, and degree of liver damage. Twenty one had chronic persistent or lobular hepatitis; 28 had chronic active hepatitis and 7 had cirrhosis. The percentages of patients who lost HBeAg at month 6, 12 and 18 were 22%, 32% and 38% in the treated group, and 16%, 20% and 37% in the controls (differences = ns). At the same time intervals, HBV-DNA detected by dot spot hybridization, cleared off in 39%, 39% and 41% of treated patients as compared to 16%, 36% and 37% of controls (difference = p < 0.05 for HBV-DNA clearance at month 6). At the end of follow-up, 12 treated patients (41%, including 8 antiHBe seroconverters) and 10 untreated controls (42%, including 6 anti-HBe seroconverters) had normal aminotransferase levels. Conclusions show that in patients with chronic hepatitis B, clearance of HBV-DNA but not of HBeAg was hastened by a 6-month treatment with low doses of recombinant alpha-2a interferon.