We examined the effect of genetic polymorphisms of phase-II enzymes, glutathione S-transferase P1 (GSTP1) and N-acetyltransferase2 (NAT2) on susceptibility to esophageal squamous-cell carcinoma To determine the genotypes of the 2 polymorphisms, PCR-based analysis was performed on samples from 66 Japanese patients who had been histologically diagnosed as having esophageal squamous-cell carcinoma, and 164 healthy Japanese controls. The frequency of the AA genotype of GSTP1 was significantly higher in esophageal-cancer patients than in the controls according to logistic-regression analysis (92% of the patients and 68% of the controls; odds ratio (OR), 8.0; p = 0.0013). Also, more patients had the slow and intermediate acetylator genotypes of NAT2 than the controls (15% and 38% vs. 10% and 32% respectively; OR of the slow acetylator genotype, 4.2; p = 0.032; OR of the slow plus intermediate acetylator genotypes, 2.9; p = 0.015). Polymorphisms of GSTP1 and NAT2 may serve as genetic biomarkers for predicting susceptibility to esophageal squamous-cell carcinoma.