STK15/BTAK/Aurora-A involved in regulating centrosomes and chromosome segregation is amplified and overexpressed in human cancers. A T91A polymorphism in STK15 causes Phe31Ile substitution, and the 31Ile variant has been shown to be preferentially amplified and associated with degree of aneuploidy in human tumors. We genotyped 656 patients with esophageal squamous cell carcinoma (ESCC) and 656 controls for the polymorphism to examine the hypothesis that the STK15 variation may affect individual susceptibility to the occurrence and aggression of ESCC. It was found that the Ile/Ile genotype was significantly associated with increased risk of ESCC occurrence [odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.36-2.85] compared with the Phe/Phe genotype. The 31Ile allele frequency significantly increased as ESCC stage increased (trend test, P = 0.006). Patients with the Ile/Ile genotype had an increased risk for invasive disease (stage II-IV; OR = 2.13, 95% CI = 1.04-4.39) or metastatic disease (stage III and IV; OR = 2.31, 95% CI = 1.06-5.05) compared with those with the Phe/Phe genotype. A positive correlation between the Ile/Ile genotype and high ESCC grade was also observed. Our results demonstrate for the first time that the STK15 polymorphism is a genetic susceptibility factor for the occurrence and aggression of ESCC.