OBJECTIVE: More and more evidence has shown that the critical functions of long non-coding RNA (IncRNA) polymorphism in the carcinogenicity mechanism of a variety of cancers. The association between IncRNA HOX transcript antisense intergenic RNA (HOTAIR) polymorphism and the risk of head and neck squamous cell carcinoma (HNSCC) in Chinese population has not been reported. To investigated the effects of HOTAIR polymorphism on cancer susceptibility, the influence of HOTAIR variants on the risk of HNSCC was analyzed in this study. PATIENTS AND METHODS: In this case-control study, thetagging SNPs(rs874945, rs4759314, and rs7958904) in HOTAIR gene were genotyped in Chinese population consisting of 366HNSCC cases and 732 controls. RESULTS: It was found that rs4759314 was associated with a significantly increased risk of HNSCC in Chinese population [GG vs. AA: adjusted odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.01-1.50; additive model: OR = 1.21, 95% CI = 1.01-1.461 However, there were no significant associations of rs874945 and rs7958904 with HNSCC risk. CONCLUSIONS: HOTAIR rs4759314 may influence HNSCC susceptibility and serve as a diagnostic biomarker.