Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) remains a significant source of morbidity and mortality. Factors that reliably predict allograft injury from HCV have not been identified. Demographics, clinical data, and histopathological characteristics of recipients with and without persistently elevated serum transaminase levels (PEST) were compared. Twenty-four patients with HCV-induced end-stage liver disease who underwent OLT between October 1995 and December 1998 were entered into a longitudinal, prospective evaluation for identification of parameters associated with graft injury. Liver biopsies were performed preoperatively and between posttransplantation days 1 to 28, 29 to 60, 61 to 180, 181 to 360, and then every 6 to 12 months thereafter. Biopsy specimens were reviewed in a blinded fashion and scored for rejection, necroinflammatory activity, extent of fibrosis, and infiltrating cell type, location, and magnitude. Transplant recipients with PEST (alanine transaminase level >1.5 times normal for 3 consecutive months) and cholestatic hepatitis showed an increased viral load compared with their own preoperative values (16-fold and 256-fold, respectively). Compared with control transplant recipients, PEST was associated with macrovesicular steatosis within 28 days after OLT (P <.05) and showed an increased rate of fibrosis (P <.003) despite similar degrees of rejection and necroinflammatory activity. There was no difference in demographics or immunosuppression. Macrovesicular steatosis may be the earliest predictor of graft fibrosis. Despite similar degrees of necroinflammatory activity, transplant recipients with PEST had an increased rate of fibrosis that could be predicted on average within 6 months posttransplantation.