Genome wide association studies (GWAS) have identified a series of genetic variants associated with the risk of esophageal adenocarcinoma (EAC)/Barrett's esophagus (BE), which was different from those loci for esophageal squamous cell carcinoma (ESCC). It is important to evaluate whether these susceptibility loci for EAC/BE are also implicated in ESCC development. In the current study, we analyzed genetic variants at 3p13, 9q22, 16q24 and 19p13 in a case-control study including 2139 ESCC patients and 2463 cancer-free controls in a Chinese population, and further characterized the biological relevance of genetic variants by functional assays. We found that the G allele of rs11789015 at 9q22, as compared with the A allele, was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.77 (95%CI, 0.65-0.90; P = 1.38 × 10), whereas the other three loci were not associated with ESCC risk. We further found that rs11789015-G allele correlated with decreased mRNA and protein levels of BARX1. Dual-luciferase reporter gene assay revealed that the A > G change at rs11789015 significantly decreased the promoter activity of BARX1. Both the mRNA and protein levels of BARX1 were significantly higher in ESCC tumor tissues compared with the corresponding normal tissues. Moreover, the deletion of BARX1 substantially reduced ESCC cells growth, migration and invasion. In conclusion, these results suggest that genetic variants at 9q22 are associated with the risk of both EAC/BE and ESCC, possibly by regulating the function of BARX1.