In 1995, the intrafamilial spread of hepatitis C virus (HCV) was evaluated among 1379 household contacts of 585 HCV antibody-positive HCV RNA-positive subjects (index cases) in Italy. All index cases were patients with histologically proven chronic liver disease. The presence of antibodies to HCV (anti-HCV) was assessed by third-generation enzyme-linked immunosorbent assay (ELISA); the polymerase chain reaction (PCR) was used to test for HCV RNA. The overall anti-HCV prevalence among household contacts of index cases was 7.3% (101/1379); it was 15.6% in spouses and 3.2% in other relatives (P < 0.05; odds ratio (OR), 6.5; 95% confidence interval (CI), 3.5-8.6). Spouses married to index cases for longer than 20 years had a significantly higher anti-HCV prevalence than those married 20 years or less (19.8% vs 8.0%; P< 0.05; OR, 2.8; 95% CI, 1.5-5.3). Parenteral risk factors were more likely to be reported in anti-HCV positive than in anti-HCV negative household contacts. After adjustment for confounders by multiple logistic regression analysis, age greater than 4 5 years (OR, 3.1; 95% CI, 1.6-5.3) and any parenteral exposure (OR, 3.7; 95% CI, 1.7-8.1), were the only independent predictors of the likelihood of anti-HCV positivity among household contacts. Spouses versus other relatives and length of marriage were both no longer associated. These findings suggest that sexual transmission does not seem to play a role in the intrafamilial spread of HCV infection.