Data from a surveillance system for type-specific acute viral hepatitis in Italy has been used to evaluate the risk of heterosexual transmission of hepatitis C virus (HCV) associated with sexual activity with multiple partners in subjects > or = 15 years of age. Hepatitis A cases were used as controls. During the period 1991-1996, 1,359 acute hepatitis C and 4,365 hepatitis A cases were recorded among subjects > or = 15 years of age. Intravenous drug use was the most frequent source of infection (35.9%) reported by HCV cases; two or more sexual partners during the 6 months before disease onset accounted for 34.9% of hepatitis C cases. Adjusting by multiple logistic regression analysis for the confounding effect of all risk factors considered (blood transfusion, intravenous drug use, surgical intervention, dental therapy, other parenteral exposure), and for age, sex, area of residence, and educational level of subjects, showed that having two or more sexual partners is an independent predictor of the likelihood of hepatitis C (OR=2.2; 95% CI=1.7-2.7). After excluding intravenous drug users and patients transfused with blood from analysis, the increase in the adjusted OR for the association between HCV and the number of sexual partners correlated with the increase in the number of sexual partners. The risk of hepatitis C was 2.0 times higher (95% CI=1.4-2.9) for subjects with two sexual partners and 2.8 times higher (95% CI=2.1-3.8) for subjects with three or more sexual partners, as compared to subjects with less than two sexual partners. These findings suggest that heterosexual transmission may play an important role in the spread of hepatitis C in Italy.