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This study aimed to explore the genetic association of polymorphisms in caveolin-1 gene (CAV1) with hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) susceptibility in a Chinese Han population.The genotyping of polymorphism was conducted using polymerase chain reaction-restriction fragment length polymorphism method. Whether the genotype distribution of polymorphisms in the healthy controls was consistent with Hardy–Weinberg equilibrium (HWE) was detected. The genotype and allele frequency difference between the 2 groups was compared by chi-square test. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to show the relative risk of HCC which resulted from genetic variants in CAV1. Moreover, the linkage disequilibrium of CAV1 polymorphisms was analyzed by Haploview.The AG genotype and A allele of rs1049334 showed significantly higher frequency in HCC patients than that of chronic HBV patients and the healthy controls (P < .05); so their carriage obviously increased the susceptibility to HBV-related HCC, irrespective of the fact whether individuals were infected with hepatitis B virus or not (AG vs GG: OR 1.958, 95% CI 1.050–3.650, OR 1.899, 95% CI 1.034–3.487; A vs G: OR 1.667, 95% CI 1.033–2.689, OR 1.777, 95% CI 1.103–2.863). Additionally, A-G haplotype of rs3807989-rs1049334 showed the protective role for HBV-related HCC (OR 0.102, 95% CI 0.035–0.293; OR 0.135, 95% CI 0.046–0.395).CAV1 rs1049334 polymorphism is significantly associated with the occurrence risk of HBV-related HCC, and the interaction of polymorphisms should not be neglected.