Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Esophageal cancer is very aggressive; genetic polymorphisms may explain in part the individual differences in esophageal cancer susceptibility. We conducted a hospital based case-control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs) in the interleukin (IL)-15 and IL-15 receptor alpha (IL-15RA) gene on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The genotypes were determined using a custom-by-design 48-Plex SNPscan(TM) kit. The IL-15RA rs2228059 A>C polymorphism was associated with a decreased risk of ESCC in a recessive genetic model; However, there was no significant association between the other five SNPs and ESCC risk. Stratified analyses indicated a significantly decreased risk of ESCC associated with the IL-15RA rs2228059 A>C polymorphism was evident among male, older, non-smoker, and non-drinker patients. These findings indicated that the functional polymorphism, IL-15RA rs2228059 A>C, might contribute to ESCC susceptibility. However, the statistical power of our study was limited because of the moderate sample size and absence of a validation cohort. Large well-designed studies are warranted to confirm our findings.