AIM: To investigate the etiology of esophageal cancer among Taiwanese women. METHODS: This is a multi-center, hospital-based, case-control study. Case patients consisted of women who were newly diagnosed and pathology-proven to have esophageal squamous cell carcinoma (ESCC) from three large medical centers (one from northern and two from Southern Taiwan, respectively) between August 2000 and December 2008. Each ESCC patient was matched with 4 healthy women based on age (within 3 years) and hospital of origin, from the Department of Preventive Medicine in each hospital. A total of 51 case patients and 204 controls, all women, were studied. RESULTS: Frequencies of smokers and drinkers among ESCC patients were 19.6% and 21.6%, respectively, which were significantly higher than smokers (4.4%) and drinkers (4.4%) among controls (OR = 4.07, 95% CI: 1.36-12.16, P = 0.01; OR = 3.55, 95% CI: 1.03-12.27, P = 0.04). Women who drank an amount of alcohol more than 158 g per week had a 20.58-fold greater risk (95% CI: 1.72-245.62, P = 0.02) of ESCC than those who never drank alcohol after adjusting for other covariates, although the sample size was small. CONCLUSION: Cigarette smoking and alcohol drinking, especially heavy drinking, are the major risks for developing ESCC in Taiwanese women.