About one third of patients with chronic hepatitis B show a sustained response when treated with interferon-α. Combining interferon-α with immunomodulators might be a way to increase response rate. The aim of this study was to compare the efficacy of lymphoblastoid interferon-α given alone with its efficacy when combined with levamisole in chronic hepatitis B. Forty-five patients with HBeAg-positive chronic hepatitis were randomly selected (with stratification for ALT levels) to receive a 6-mo course of combination therapy with lymphoblastoid interferon-α (5 million units/m2 three times per week) and levamisole (150 mg three times per week) or lymphoblastoid interferon at the same dose regimen and a matching placebo. Final evaluation 18 mo after randomization revealed a loss of both HBeAg and hepatitis B virus DNA with ALT normalization in 38% of patients treated with interferon-α alone and in 10% of patients receiving combination therapy. The higher response rate observed in patients treated with interferon-α alone was maintained after stratification for basal ALT levels (i.e., higher [45% vs. 10%] or lower [31% vs. 9%] than three times the upper normal value). The length of time to sustained HBeAg clearance was significantly (p < 0.05) shorter in patients receiving monotherapy than in patients receiving combination therapy. Blinded histological assessment revealed improvement in 44% of patients treated with interferon-α alone compared with improvement in 6% of patients receiving combination therapy. These results indicate that levamisole has no additive effects when combined with interferon-α in the treatment of HBeAg-positive chronic hepatitis. (HEPATOLOGY 1992;16:1115–1119.)