Objective: Acute hepatitis B virus (HBV) infection is a self-limiting disease which usually recovers within 4-12 weeks. At the present moment, there is no specific treatment of acute HBV infection. This study investigates the efficacy of interferon-alpha (IFN) therapy in acute prolonged HBV infection to prevent its progression into chronic stage., Methods: We enrolled a total number of 54 patients for the study in the span of 8 years. Group A patients (n = 20) received IFN-alpha 5 million units (MU) subcutaneously (s.c.) thrice a week for 12 weeks and Group B patients (n = 34) were placed on placebo therapy as control for 12 weeks, with a follow-up for one year., Results: Seroconversion (disappearance of HBsAg, HBeAg, serum HBV DNA and appearance of anti-HBe) in Group A occurred in 16 patients (80%) within 24 weeks of illness, whereas in Group B seroconversion was observed only in 18 patients (53%) within 24 weeks. During follow-up upto one year, two more patients showed seroconversion in Group A but none in Group B. While on treatment no casualty was reported in Group A but one patient died of hepatic coma in Group B. Our observation revealed that in acute prolonged (> 12 weeks but < 24 weeks) hepatitis B, spontaneous seroconversion rate was 53% but with moderate dose of IFN therapy (5 MU, s.c., thrice weekly) from 12 weeks onwards, the seroconversion rate came out to be 80% (upto 24 weeks) which increased upto 90% when followed-up for one year., Conclusions: IFN-alpha treatment in acute prolonged (> 12 weeks) HBV infection is safe and may prevent its progression to the chronic stage.