Hepatitis C virus (HCV) frequently leads to chronic hepatitis, cirrhosis, and hepatocellular carcinoma, but the mechanism of liver injury is unknown. To determine whether replication of HCV is related to liver damage, we studied 17 liver biopsy specimens (six anti-HCV-positive chronic persistent hepatitis specimens, seven anti-HCV-positive chronic active hepatitis specimens, and four anti-HCV-negative controls) by reverse transcription followed by double polymerase chain reaction for the 5' nontranslated regions of the genomic and replicative strands of HCV. The histologic activity index as well as lymphoid aggregates in portal tracts, bile duct damage, and fatty change were assessed semiquantitatively. There was a statistically significant correlation between the presence of HCV RNA sequences in liver tissue and anti-HCV antibody in serum (P < .005). No correlation was detected between the histologic activity index or any individual histologic parameters and the presence of genomic or replicative strands of HCV. These findings suggest that a direct viropathic effect is less important than other mechanisms, such as the host immune response, in the pathogenesis of hepatocyte and bile duct injury in chronic hepatitis.