The reasons for wide variations in the severity of recurrent hepatitis C after liver transplantation are unclear. We studied liver transplant recipients to assess the effect of hepatitis C virus (HCV) genotype and HCV RNA quantification on histologic progression of recurrent hepatitis C after transplantation. Twenty-five patients underwent transplantation for HCV cirrhosis and were followed up with virologic and histologic assessments for a mean of 51 months. HCV genotype was determined by line probe assay. HCV RNA was quantitated in serum samples by nested polymerase chain reaction. The HCV genotype 1 was detected in 17 patients and other genotypes in 8. Acute lobular hepatitis developed in 17 patients 162 days posttransplantation on average. Long-term biopsy specimens (mean, 51 months after the date of liver transplantation; range, 24-86 months) showed chronic hepatitis in 19 patients (mild, 5; moderate, 9; and severe, 5, 2 with extensive scarring). The serum alanine aminotransferase level was correlated with hepatocyte necrosis (piecemeal and lobular) but not with portal inflammation or fibrosis. Patients infected with genotype 1 had a higher Knodell score, and the 5 patients with severe hepatitis C all were infected with genotype 1. HCV RNA levels were significantly higher in patients with genotype 1 than in patients with other genotypes, as were the severity of histologic recurrence and levels of viral replication.