To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.