The aim of this study was to analyze the effect of human leukocyte antigen (HLA) matching on outcome, severity of recurrent hepatitis C and risk of rejection in hepatitis C positive patients after liver transplantation (LT). In a retrospective analysis, 165 liver transplants in patients positive for hepatitis C virus (HCV) with complete donor/recipient HLA typing were reviewed for recurrence of HCV and outcome. Follow-up ranged from 1 to 158 months (median, 74.5 months). Immunosuppression consisted of either cyclosporine-A- or tacrolimus-based quadruple induction therapy including or an interleukin 2-receptor antagonist. Protocol liver biopsies were performed after 1, 3, 5, 7, and 10 years and staged according to the Scheuer scoring system. The overall 1-, 5-, and 10-year graft survival figures were 81.8%, 69.11 and 62%, respectively. There was no correlation in the study population between number of HLA mismatches and graft survival. The number of rejection episodes increased significantly in patients with more HLA mismatches (P < 0.05). In contrast to this, the fibrosis progression was significantly faster in patients with 0–5 HLA mismatches compared to patients with a complete HLA mismatch. In conclusion, HLA matching did not influence graft survival in patients after LT for end-stage HCV infection, however, despite less rejection episodes, the fibrosis progression increased in patients with less HLA mismatches within the first year after LT. Liver Transpl 12:644–651, 2006. © 2006 AASLD.