HOX transcript antisense intergenic RNA (HOTAIR) has been widely regarded as a functional lncRNA contributing to multiple cancers. However, few studies have examined the effect of single nucleotide polymorphisms (SNPs) in HOTAIR on the occurrence and development of hepatocellular carcinoma (HCC). In this study, three potentially functional HOTAIR SNPs (rs17105613, rs12427129, and rs3816153) were selected using bioinformatic tools. A case‐control study including 1262 cases and 1559 controls was conducted to explore the association of HOTAIR SNPs with the risk of HCC in a Southern Chinese population. We found that SNPs rs12427129 and rs3816153 were associated with the risk of HCC in dominant genetic models (CC: CT + TT, adjusted odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.57–0.90 and GG: GT + TT, adjusted OR = 1.30, 95%CI = 1.08–1.57). Additionally, SNP–environment interactions for rs12427129, rs3816153, and HBsAg status were found to enhance the risk of HCC, with FDR‐P as an additive interaction equal to 0.0006 and 0.0144, respectively. In multifactor dimensionality reduction (MDR) analysis, the three‐factor model (HBsAg status, rs12427129 and rs3816153) yielded the highest test accuracy of 77.74% (permutation P < 0.001). Interestingly, the effect of rs12427129 and rs3816153 on the risk of HCC could be modified by HBsAg status, while the rs12427129 CT/TT genotype could antagonize the detrimental effect of rs3816153 GT/TT genotype on HCC. Our findings suggest that rs12427129 and rs3816153, including their SNP‐SNP and SNP‐environment interaction with HBsAg status, potentially play important roles on the susceptibility to HCC.