Recurrence of hepatitis C after liver transplantation is common and can lead to severe liver diseases. Although immunosuppression and high levels of viremia suggest a direct pathogenicity of hepatitis C virus (HCV), the relations between viral replication and long-term histological course are still unknown. Thirty-three patients with a mean histological follow-up of 3.5 years (3 months - 8.6 years) were analyzed. Nineteen patients were infected by genotype 1b. Liver HCV RNA was determined in parallel with the quantitation of an internal control (28S ribosomal RNA) by competitive polymerase chain reaction (PCR). Lobular hepatitis (LH) and chronic active hepatitis (CAH) occurred in 27 and 19 patients, respectively. Levels of liver HCV RNA determined in 84 biopsies were higher in cases of LH than in the other patterns (82 +/- 123 vs. 19 +/- 38; P < .01) and were unrelated to the genotype. Progression from LH to CAH was associated with a highly significant decrease of liver HCV RNA (P = .006), which was not observed in patients with stable histology. Among patients with CAH, those infected by genotype 1b had more severe liver damage and lower levels of liver HCV RNA than others (P = .04). Multivariate analysis showed that high levels of liver HCV RNA at the time of the first posttransplantation biopsy was an independent predictor of CAH (P = .01). After liver transplantation, the progression to CAH together with a decrease of liver HCV RNA suggests that a host's response is involved in the long-term viral pathogenicity. This response may be stronger and liver disease more severe in patients with high levels of replication at the time of LH and in those infected by genotype 1b.