GSTM3 is involved in detoxification of carcinogens and may be important in modulating cancer susceptibility. GSTM3 genotype frequencies were determined in peripheral blood DNA of 149 esophageal cancer patients and 200 nonmalignant controls using the PCR followed by PAGE. Patients who were heterozygous carriers of GSTM3 AB genotype had an enhanced risk for developing esophageal cancer [odds ratio (OR), 2.1; 95% confidence interval (95% CI), 1.1-3.7; P = 0.01]. In males, the risk due to GSTM3 AB genotype increased further (OR, 3.4; 95% CI, 1.7-6.8; P = 0.000). Interaction of GSTM3 AB + BB and GSTM1 null genotypes marginally modulated risk (OR, 2.3; 95% CI, 1.1-3.7; P = 0.01). Association with histology (adenocarcinoma: OR, 3.4; 95% CI, 1.1-10.9; P = 0.03) and tumor site (middle third location: OR, 2.2; 95% CI, 1.1-4.4; P = 0.01; lower third location: OR, 2.6; 95% CI, 1.2-5.6; P = 0.01) was also documented. Our results suggest that GSTM3 polymorphism may influence esophageal cancer susceptibility, in particular modulating the risk for adenocarcinoma histology and tumors of the mid and lower third region.