Hepatitis viruses and alcohol are major causes of liver disease. This study was aimed at investigating the effect of alcohol intake on the replication of hepatitis C virus and the efficacy of interferon therapy. Fiftythree patients who were histologically proved to have chronic hepatitis C were tested. Of these, 16 were diagnosed as habitual drinkers whose cumulative total consumption of alcohol was more than 100 kg or who had consumed at least 60 gm of ethanol daily for at least 5 yr. The quantities of hepatitis C virus RNA in serum were measured with a competitive assay that combined reverse transcription and polymerase chain reaction. The subjects received a 26-wk course of interferon-α therapy. There were no significant differences in age and ALT levels between habitual drinkers and nonhabitual drinkers. The titer of viral RNA (logarithmic transformed copy numbers per milliliter of serum) of habitual drinkers (8.5 ± 0.5) was higher than that of nonhabitual drinkers (7.7 ± 0.8) (p < 0.01). Neopterin levels in serum, a marker for the activation of cellmediated immunity, were lower for habitual drinkers (5.7 ± 1.5 pmol/ml) than for nonhabitual drinkers (8.1 ± 5.0 pmol/ml) (p < 0.01). Eleven of the nonhabitual drinkers (30%) were long-term responders whose alanine aminotransferase levels remained within normal range during the 24 wk after interferon therapy, whereas only one (6%) of the habitual drinkers was a long-term responder (p = 0.06). These findings suggest that alcohol intake increases hepatitis C virus RNA levels in serum—at least in part—impairment of cellular immunity, and modulates the efficacy of interferon therapy. (Hepatology 1994;20:1115–1120).