We compared tissue hepatitis C virus (HCV) RNA polymerase chain reaction quantification and HCV immunohistochemistry (IHC) to histology in biopsy tissues in order to differentiate between acute rejection and HCV hepatitis recurrence early after orthotopic liver transplantation (OLT). We analyzed the first biopsy performed because of alteration of serum aminotransferases in 65 consecutive OLT patients with HCV genotype 1b. In the histological analysis, we quantified the portal tracts, Councilman bodies, Councilman body/portal tract (CP) ratio, steatosis, and Knodell and Ishak scores. The 52 patients (80%) with histological HCV recurrence [recurrence-positive (Rec+)] were separated from the 6 (9%) with acute rejection and the 7 (11%) with undetermined pathological features [recurrence-negative (Rec-)]. HCV RNA strongly correlated with HCV IHC, regardless of the histological diagnosis (P < 0.001). Both HCV RNA and HCV IHC were significantly associated with CP ratio (P = 0.041 and P = 0.008). No statistical correlation was found between HCV RNA, HCV IHC, and the other histopathologic features or the hepatitis scores. HCV RNA, HCV IHC, and CP ratio were the only variables able to discriminate between Rec+ and Rec- patients (Mann-Whitney test P < 0.001, P < 0.001, P = 0.014). In conclusion, a combined evaluation of histology, tissue HCV RNA, and HCV IHC significantly discriminated between OLT patients with or without HCV recurrence.