The aim of this study was to explore the association of C20orf54 functional single nucleotide polymorphism (SNP) with the susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern China population. The C20orf54 SNP was genotyped by direct sequencing in 240 cancer patients and 198 controls in northern China. The results showed that drinking status, family history of ESCC, and body mass index have great influence on the risk of developing ESCC. The overall genotype frequencies of C20orf54 in ESCC patients have a significant difference with healthy controls (χ2 = 8.06, P = 0.018). By using C/C genotype as the reference, the C/T genotype showed a significantly decreased risk to the development of ESCC. Thus, compared with the C/C genotype, smokers, drinkers with C/T genotype significantly decreased the risk of developing ESCC. A positive family history of ESCC with C/T and T/T genotype both increased the risk of developing ESCC. Body mass index between 18.5 and 24 with C/T genotype significantly decreased the risk of developing ESCC. The present study suggests that the C20orf54 functional SNP might be associated with a risk of development in ESCC.