The comparative efficacy of prednisolone followed by interferon alfa (IFN-α) versus IFN-α alone in enhancing the rate of antibody to hepatitis B e antigen (anti-HBe) seroconversion has not been evaluated in a large cohort of white children. To determine this, a multicenter-controlled trial was conducted in 95 hepatitis B virus (HBV)-DNA/hepatitis B e antigen (HBeAg)-positive children (median age, 9 years [range, 2-16 years]; 56 boys; 84 [89 %] white), all having inflammatory changes on liver biopsy. Patients were randomized to receive either prednisolone followed by IFN-α (n = 34); placebo followed by IFN-α (n = 30); or no treatment (n = 31). The prednisolone/placebo was given on a double-blind basis. Lymphoblastoid IFN-α was given at 5 MU/m(2) three times a week for 12 weeks. Baseline clinical, biochemical, and histological features were similar for the three groups. The majority (85 %) had a baseline aspartate aminotransferase (AST) level ≤ 100 IU/L. On follow-up between 12 and 18 months (median, 15 months) after treatment, the loss of HBeAg with anti-HBe seroconversion was more common in patients pretreated with steroids (12 of 34 [35 %]) or placebo [12 of 30 (40 %)] as against controls (4 of 31 [13 %], P< .05). Factors predictive of anti-HBe seroconversion were baseline HBV-DNA concentration of ≤ 1,000 pg/mL and a greater degree of portal tract inflammation on pretrial biopsy. Our results show that in white children treatment with IFN-α, at the dose and duration used in this study, improves the rate of anti-HBe seroconversion. Steroid priming does not potentiate the effect of IFN-α.