The effectiveness of corticosteroid withdrawal therapy (CSWT), with or without follow-up interferon-alpha (IFN-alpha), has not been reported for HBe antigen (HBeAg) -positive patients with chronic hepatitis B. We conducted a prospective randomized controlled trial in 42 patients with HBeAg- and HBV-DNA-positive chronic hepatitis B (HBV genotype C: 38 patients) to assess the possible additive effect of follow-up IFN-alpha after CSWT compared with CSWT alone. HBeAg seroconversion rates in the CSWT-alone and the combination group were 11.1% vs 11.8% at 24 weeks, 27.8% vs 12.5% at 52 weeks, 33.3% vs 18.8% at 76 weeks, and 38.9% vs 18.8% at 104 weeks, respectively. The final HBeAg seroconversion rates after CSWT alone were twice those following combination therapy. We conclude that CSWT alone is a very short-term treatment of just three weeks that may be more effective for long-term clinical remission than CSWT followed by IFN-alpha in Japanese genotype C-dominant hepatitis B patients.