Outcomes of infection with hepatitis C virus (HCV) vary widely, from asymptomatic clearance to chronic infection, leading to complications that include fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Previous studies have reported statistical associations between human leukocyte antigen (HLA) heterozygosity and favorable outcomes of infection with either hepatitis B virus (HBV) or human immunodeficiency virus (HIV) (the “heterozygote advantage”). To investigate whether HLA zygosity is associated with outcome of HCV infection, we used data from the United States Organ Procurement and Transplantation Network database of 52,435 liver transplant recipients from 1995 through 2005. Of these, 30,397 were excluded for lack of HLA data, retransplantation, known HIV infection, or insufficient information regarding HBV infection. The remaining cases were analyzed for associations between HCV infection and HLA zygosity with 1‐sided Fisher's exact tests. Results show significantly lower proportions of HLA‐DRB1 heterozygosity among HCV‐infected than uninfected cases. The differences were more pronounced with alleles represented as functional supertypes (P = 1.05 × 10⁻⁶) than as low‐resolution genotypes (P = 1.99 × 10⁻³). No significant associations between zygosity and HCV infection were found for other HLA loci. Conclusion: These findings constitute evidence for an advantage among carriers of different supertype HLA‐DRB1 alleles against HCV infection progression to end‐stage liver disease in a large‐scale, long‐term study population. Considering HLA polymorphism in terms of supertype diversity is recommended in strategies to design association studies for robust results across populations and in trials to improve treatment options for patients with chronic viral infection. Access to deidentified clinical information relating genetic variation to viral infection improves understanding of variation in infection outcomes and might help to personalize medicine with treatment options informed in part by human genetic variation. (HEPATOLOGY 2007.)