AIM:To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of Gansu Province, in Chinese males. METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYP2E1 *c1/*c2, ALDH2 *1/*2 and ADH1B *1/*1 genotypes). A total of 80 esophageal cancer cases and 480 controls were recruited. RESULTS: Compared with controls, cases had a greater prevalence of heavier alcohol consumption (53.8% vs 16.2%) and a higher proportion of alcohol drinkers with > 30 drink-years (28.8% vs 13.5%). Heavier alcohol consumption and alcohol drinking with > 30 drink- years increased the risk of ESCC, with ORs (95% CI) of 3.20 (1.32-9.65) and 1.68 (0.96-3.21). CYP2E1 (*c1/*c1), ALDH2 (*1/*2) and ADH1B (*1/*1) genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance (P = 0.014; P = 0.094; P = 0.0001 respectively). There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 *1/*2 as well as ADH1B encoded by ADH1B *1/*1 and CYP2E1 encoded by CYP2E1 *c1/*c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 (*1/*1 genotype) as well as ADH1B (*1/*2 + *2/*2) and CYP2E1 (*c1/*c2 + *c2/*c2) genotypes, with a statistically significant difference; ORs (95% CI) of 8.58 (3.28-22.68), 27.12 (8.52-70.19) and 7.64 (2.82-11.31) respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 (*1/*2) combined the ADH1B (*1/*1) genotype or ALDH2 (*1/*2) combined the CYP2E1 (*c1/*c1) genotype leads to synergistic interactions, higher than drinkers with ALDH2 (*1/*1) + ADH1B (*1/*2 + *2/*2), ALDH2 (*1/*1) + CYP2E1 (*c1/*c2 + *c2/*c2) respectively , ORs (95% CI) of 7.46 (3.28-18.32) and 6.82 (1.44-9.76) respectively. Individuals with the ADH1B combined the CYP2E1 genotype showed no synergistic interaction. CONCLUSION: In our study, we found that alcohol consumption and polymorphisms in the CYP2E1, ADH1B and ALDH2 genes are important risk factors for ESCC, and that there was a synergistic interaction among polymorphisms in the CYP2E1, ALDH2 and ADH1B genes and heavy alcohol drinking, in Chinese males living in Gansu Province, China. AIM: To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of ​​Gansu Province, in Chinese males. METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYP2E1 * c1 / * c2, ALDH2 * 1 / * 2 and ADH1B * 1 / * 1 genotypes). A total of 80 esophageal cancer cases and 480 controls were recruited. had a greater prevalence of heavier alcohol consumption (53.8% vs 16.2%) and a higher proportion of alcohol drinkers with> 30 drink-years (28.8% vs 13.5%). Heavier alcohol consumption and alcohol drinking with> 30 drink- years increased the risk of ESCC with ORs 95% CI of 3.20 1.32-9.65 and 1.68 0.96-3.21. CYP2E1 (* c1 / * c1), ALDH2 (* 1 / * 2) and ADH1B 1) genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to the statistical significance (P = 0.014; P = 0.094; P = 0.0001 re There are synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 * 1 / * 2 as well as ADH1B encoded by ADH1B * 1 / * 1 and CYP2E1 encoded by CYP2E1 * c1 / * c1 was higher than that in the never / rare-to-light drinkers with an active ALDH2 (* 1 / * 1 genotype) as well as ADH1B ORs (95% CI) of 8.58 (3.28-22.68), 27.12 (8.52-70.19) + CYP2E1 (* c1 / * c2 + * c2 / * c2) genotypes with a statistically significant difference and 7.64 (2.82-11.31) respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 (* 1 / * 2) combined the ADH1B (* 1 / * 1) genotype or ALDH2 (* 1 / * 2) The CYP2E1 (* c1 / * c1) genotype leads to synergistic interactions, higher than drinkers with ALDH2 (* 1 / * 1) + ADH1B (* 1 / * 2 + * 2 / * 2) Respectively. ORs (95% CI) of 7.46 (3.28-18.32) and 6.82 (1.44-9.76) respectively. Individuals with the (1) + CYP2E1 (* c1 / * c2 + * c2 / * c2)ADH1B combined the CYP2E1 genotype showed no synergistic interaction. CONCLUSION: In our study, we found that alcohol consumption and polymorphisms in the CYP2E1, ADH1B and ALDH2 genes are important risk factors for ESCC, and that there was was synergistic interaction among polymorphisms in the CYP2E1 , ALDH2 and ADH1B genes and heavy alcohol drinking, in Chinese males living in Gansu Province, China.