Genetic factors are known to be important in the development of esophageal squamous cell carcinoma (ESCC). Epidermal growth factor (EGF) can activate several signaling pathways leading to proliferation, differentiation, and tumorigenesis of epithelial tissues by binding with its receptor. Interindividual variations in EGF production were genetically contributed to EGF +61 G/A polymorphism. The purpose of this study is to investigate the potential association between EGF gene polymorphism and ESCC in a Chinese population. In this study, we analyzed single nucleotide polymorphism of EGF +61 G/A in 158 patients with ESCC and 212 age- and sex-matched controls in a Chinese population using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and DNA sequencing. The variant genotypes of GA/AA were associated with a significantly decreased risk of ESCC compared with the wild-type homozygote GG (OR = 0.657, 95% CI: 0.434-0.996). However, no significant difference was observed between the EGF +61 G/A polymorphism and the risk of ESCC when the analyses were stratified in terms of age, gender, smoking status, different clinical stage, and lymph node status. The EGF +61 G/A polymorphism is associated with ESCC in a Chinese population. Our data suggests that the EGF gene may play a role in the development of ESCC.