Polymorphisms of the nucleotide excision repair gene XPD are candidates for influencing cancer susceptibility. To determine the effect of XPD genetic polymorphisms on the risk of esophageal squamous cell carcinoma (ESCC) and its interaction with carcinogen exposure, XPD polymorphisms at codon 312 (Asp→Asn) and codon 751 (Lys→Gln) were determined in 135 ESCC patients and 152 normal controls. Polymorphism at codon 312 made no contribution to genetic risk for ESCC. Our results showed that there was a significant difference between frequencies for XPD 751 Gln/Gln genotype in ESCC patients (8.9%) and normal cases (1.3%), and that Gln/Gln genotype was associated with an increased risk of ESCC (odds ratio [OR]=6.71; 95% confidence interval [CI]: 1.90-23.73). The results of the logistic regression model showed that XPD 751 Gln/Gln genotype and drinking were candidates for influencing the risk of ESCC. Among smokers, the risk of ESCC in XPD 751 Gln/Gln genotype increased 8-fold than that XPD 751 Lys/Lys genotype (OR=8.42, 95% CI: 1.02-69.58). The results indicated that XPD 751 Gln/Gln genotype may be contributing factors in the risk of ESCC and may modify risk attributable to environmental exposures.