We conducted a genome-wide association study to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non-HCC controls using the Axiom-CHB genome-wide array. After identifying single-nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period 1991-2013 in a community-based cohort for evaluating long-term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single-nucleotide polymorphisms in the proximity of HLA-DQB1 were associated with HCC (P < 8.7 × 10 ) in the genome-wide association study. Long-term follow-up showed a significant association with HLA-DQB103:01 and DQB106:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB103:01 and DQB106:02, respectively. After stratification by HCV genotypes, DQB103:01 showed protective effects only in patients with HCV genotype 1, whereas DQB106:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA-DRB115:01, which is in linkage disequilibrium with DQB106:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31-2.93). Haplotype analysis supported that DQB103:01 and DQB106:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA-DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. (Hepatology 2018;67:651-661).