We have investigated the efficacy of recombinant alpha-interferon treatment of chronic hepatitis B virus (HBV) infection in two therapeutic trials. Forty-four patients positive for HBsAg, HBeAg, DNA polymerase and HBV-DNA were studied. Fourteen carriers were treated in the first trial with doses ranging from 18 to 50 million units (mu)/m2 3 times per week. Six of 14 treated carriers (43%) have a sustained loss of HBeAg, HBV-DNA and DNA polymerase. Four lost HBsAg (29%). Two of 11 (18%) untreated carriers lost HBeAg, but none lost HBsAg (P = 0.05). Nineteen patients were entered in a second trial to assess dose response. Fourteen were treated with doses ranging from 2.5 to 10 mu/m2. Five patients were untreated. Two treated patients seroconverted to anti-HBe, and a third cleared HBsAg and seroconverted to anti-HBs. None of the controls was anti-HBe-positive. Thus 9/28 (32%) carriers have lost replicating HBV versus 2/16 (13%) of untreated patients. Elevated pretreatment serum ALT concentrations and severe chronic active hepatitis were associated with inhibition of viral replication in treated patients suggesting that seroconversion may require an appropriate host response. The efficacy of recombinant interferon is restricted, but it may be of benefit in a proportion of carriers.