The significance of antibodies to hepatitis C virus in patients with chronic alcoholic liver disease is unclear. Prior studies have utilized the first-generation enzyme-linked immunosorbent assay, which is limited by problems with sensitivity and specificity. Hepatitis C virus infection in 137 patients with biopsy-proven alcoholic liver disease was assessed with second-generation hepatitis C virus antibody assays and reverse transcription-polymerase chain reaction for detection of hepatitis C virus RNA in the serum. The patients were categorized into three groups according to results of serological testing. Discriminant-function analysis was used to determine which factors (risk, biochemical and histological) could best differentiate the three groups. Thirty-three patients were reactive on secondgeneration enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay and RNA positive (group 1). Twelve were reactive on second-generation enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay but RNA negative (group 2). Eighty-six were nonreactive on second-generation enzyme-linked immunosorbent assay, and six were reactive on second-generation enzyme-linked immunosorbent assay but negative on second-generation recombinant immunoblot assay and negative for hepatitis C virus RNA (group 3). Seventy-six percent of patients in group 1 and 58 in group 2 had parenteral risk factors, compared with only 1 in group 3 (p < 0.00001). The mean ALT level was higher in group 1 patients (p < 0.05). The mean histologic activity index was significantly higher in group 1 (p = 0.0007). Periportal and bridging necrosis and portal inflammation were significantly increased in group 1 (p = 0.0004 and p = 0.002, respectively). We found no significant difference in intralobular degeneration and focal necrosis or fibrosis among the three groups. The histological and biochemical features of groups 2 and 3 were similar. Most patients with alcoholic liver disease with concomitant hepatitis C infection have an identifiable parenteral risk factor. Patients with viremia have histological evidence of chronic hepatitis superimposed on alcoholic liver disease. The histological features of hepatitis C virus antibody-reactive patients without viremia resemble those of patients without serological evidence of hepatitis C virus infection. (Hepatology 1994;19:554–557).