Although recurrent hepatitis C (HCV) occurs universally after liver transplantation (LT), its tempo and severity are variable and unpredictable. Diagnosis and treatment of early acute rejection (EAR) likely affect the course of recurrent HCV disease. We have studied a contemporary cohort of LT recipients to reexamine risk factors for EAR. We hypothesized that HCV etiology may represent a significant risk factor for EAR for many reasons. First, recurrent disease commonly causes biochemical abnormalities prompting allograft biopsy. Second, overlapping histologic features of acute rejection and recurrent HCV ambiguity may result in diagnostic ambiguity. Finally, the biology of hepatitis may precipitate an antidonor response in addition to an antiviral response. Records of 285 adult recipients undergoing primary LT for cirrhosis between January 1, 1999, and December 31, 2002, were retrospectively reviewed. EAR was defined as a biopsy-proven or an empirically treated episode within 6 months of LT. Cox proportional hazards analysis identified donor, recipient, transplant, and posttransplant characteristics associated with EAR; Kaplan-Meier analysis was used to assess rejection by etiology. HCV cirrhosis was the etiology for 51% of all LT recipients. There were 135 episodes of EAR (127 biopsy proven) in 117 recipients for an overall incidence of 41%. Patient groups with HCV and cholestatic / autoimmune disease groups exhibited the highest incidence of rejection at 49%. Recipient gender, ethnicity, etiology, LT year, and posttransplant immunosuppression levels were risk factors for EAR in univariate analysis; HCV etiology and female gender remained robust risk factors in multivariate analysis. Interferon-based therapy did not impact the incidence or timing of EAR. In conclusion, HCV etiology is strongly associated with EAR. HCV allograft reinfection may create an immunologic environment predisposed to EAR. Alternatively, the association of HCV and EAR may result from an increased frequency of allograft biopsy and may be further exacerbated by inability to accurately diagnose EAR in the setting of recurrent HCV.