Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide. However, the exact molecular mechanism of HCC remains uncertain. Caveolin-1 (CAV1) is the main protein in the caveolin family and plays an important role in tumorigenesis signaling. However, the contribution of CAV1 genetic variants to HCC is still unknown. The purpose of this study was to evaluate the association between the tagSNPs of the CAV1 gene and HCC risk. In this case-control study, we enrolled 1,000 HCC patients and 1,000 cancer-free controls, which were frequency-matched by age, gender, and HBV infection status. We found that CAV1 rs729949 was statistically associated with increased risk of HCC (odds ratio (OR) = 1.28; 95% confidence interval (CI), 1.11-1.48; P = 8.53 × 10(-4)), even after Bonferroni correction (P = 5.97 × 10(-3)); the expression levels of CAV1 in cancer tissues were significantly lower than those in adjacent normal tissues (P = 0.012). We also detected a significant association for CAV1 rs3807989 under the log-additive model (OR = 0.85; 95% CI, 0.74-0.98; P = 0.026). Significant associations were also detected for CAV1 rs6466583 (GG vs AA: OR = 2.53; 95% CI, 1.24-5.17; P = 0.011) and CAV1 rs3807986 (AG vs AA: OR = 3.16; 95% CI, 1.68-5.91; P = 3.36 × 10(-4)) among genotype comparisons. These findings indicated that genetic variants n CAV1 might contribute to HCC susceptibility.