Interferon-α therapy leads to HBeAg seroconversion in only one third of patients with chronic hepatitis B. In an attempt to increase the seroconversion rate, we investigated the combination of interferon-α and zidovudine in a subset of patients with presumably low response rates for interferon-α monotherapy. In a double-blind, controlled trial, 24 HBeAg-positive patients were randomized to receive lymphoblastoid interferon-α in subcutaneous doses increasing to 5 MU daily, combined with zidovudine given orally in doses increasing from 500 to 1,000 mg/day or with placebo for 16 wk. Treatment effects were monitored by quantitative assessment of HBV DNA, HBeAg and HBV DNA polymerase. Six months after termination of therapy, 1 of 12 (8%; 95% confidence interval = 2% to 39%) patients treated with interferon-α plus zidovudine and 2 of 12(17%; 95% confidence interval 2% to 48%) patients from the control group exhibited responses (HBeAg seroconversion). All patients remained HBsAg positive. The only responder of the interferon-α–zidovudine group relapsed after cessation of therapy, so none of the zidovudine-treated patients were HBeAg negative at the end of follow-up. No significant difference in AST level or in any of the virological markers was observed between the two groups during the course of the study. Adverse effects (anemia, leukopenia) necessitated reduction in the dose of zidovudine in 50% and of interferon-α in 42% of the patients treated with interferon-α plus zidovudine; in the control group these rates were 0% for placebo and 8% for interferon-α. In conclusion, the antiviral effect of interferon-α in chronic hepatitis B was not enhanced by additional zidovudine treatment. The combination therapy induced considerable side effects leading to dose reduction for both zidovudine and interferon-α. For combination therapy with interferon-α, oral nucleoside analogs with more potent antiviral effects and less toxicity than zidovudine should be developed. (HEPATOLOGY 1993;17:383–388.)