Background: The STK15 gene located on chromosome 20q13.2 encodes a centrosome-associated kinase critical for regulated chromosome segregation and cytokinesis. Recent studies have demonstrated STK15 to be significantly associated with many tumors, with aberrant expression obseved in many human malignancies. The purpose of this study was to investigate expression of STK15 in esophageal squamous cell carcinomas (ESCCs) in a Mongolian population. Methods: Two non-synonymous single nucleotide polymorphisms in the coding region of STK15, rs2273535 (Phe31Ile) and rs1047972 (Val57Ile) were assessed in 380 ESCC patients and 380 healthy controls. We also detected STK15 mRNA expression in 39 esophageal squamous cell carcinomas and corresponding adjacent tissues by real time PCR. Results: rs2273535 showed a significant association with ESCC in our Mongolian population (rs227353, P allele = 0.0447, OR (95%CI) = 1.259 (1.005~1.578)). Real time PCR analysis of ESCC tissues showed that expression of STK15 mRNA in cancer tissues was higher than in normal tissues (p = 0.013). Conclusions: Our study showed that functional SNPs in the STK15 gene are associated with ESCC in a Mongolian population and up-regulation of STK15 mRNAoccurs in ESCC tumors compared adjacent normal tissues. STK15 may thus have an important role in the prognosis of ESCC and be a potential therapeutic target.