The purpose of this study was to explore the relationship between human leukocyte antigen (HLA) compatibility and liver transplantation outcomes by analyzing the effect of HLA compatibility on 5-year graft survival. We analyzed first liver transplants between 1987 and 2002 in the Organ Procurement and Transplantation Network (OPTN) database, where A, B, or DR loci data were available. Graft failure was defined as retransplantation or death from transplant-related cause. We evaluated associations between total and locus-specific match levels and 5-year graft survival. Multivariable Cox proportional-hazard models were used to evaluate statistical interactions and adjust for the effect of potential confounders. Among 29,675 first-time transplants, the overall degree of HLA match had no effect on 5-year graft survival, even after controlling for potential confounders. Univariate and multivariable analyses showed that the 0 HLA antigen mismatch cohort of patients had higher 5-year graft failure rates than the other 6 antigen mismatch groups. However, this occurred in a small group with a disproportionately large number of live donors and split-liver recipients. When these recipients were excluded from the analysis, the effect was no longer seen. Finally, multivariable, locus-specific analyses showed no association between 5-year graft survival and degree of match/mismatch and the A, B, or DR loci. In conclusion, this careful examination of the OPTN database, with respect to HLA match or mismatch and liver graft survival, reaffirms that HLA matching has no clinically significant impact on this outcome. Liver Transpl 12:652–658, 2006. © 2006 AASLD.