In 2003 esophageal cancer was the sixth leading cause of death among men in Taiwan, but it is the fastest increasing (70%) alimentary tract cancer. The aim of this study was to investigate the impact of different habits of betel nut chewing on esophageal squamous cell carcinoma (SCC) and its interaction with cigarette use and alcohol consumption. All 165 cases were pathologically proven esophageal SCC patients (all male, mean age = 56.0, range = 35-92 years) diagnosed by biopsy during gastroendoscopic examinations. The control group comprised 255 subjects (all male, mean age = 54.8, range = 40-92 years) selected from patients who had visited the Otolaryngology Outpatient or Inpatient Department of KMUH owing to a benign lesion over this field. All were interviewed to collect demographic and substance use information by a trained interviewer using a standardized questionnaire. Smoking (aOR = 5.4, 95% CI = 2.4-12.9, PAR = 72%), alcoholic beverage drinking (aOR = 17.6, 95% CI = 9.3-35.2, PAR = 76%) and low education level are independent risk factors for esophageal cancer. Although betel nut chewers only had a borderline significant higher risk than nonchewers (aOR = 1.7; 95% CI = 0.8-3.1), those who chewed with a piece of betel inflorescence (aOR = 4.2, 95% CI = 1.4-16.0) and swallow betel-quid juice (aOR = 3.3, 95% CI = 1.3-9.3) had a significant higher risk. Significant dose-response effects were found in daily quantity of drinking and smoking. There is a synergistic effect of these three substances on the development of esophageal cancer. Betel nut chewing plays a relevant role in the development of esophageal SCC but adds to the carcinogenetic effect of smoking and alcohol drinking. Direct mucosal contact of betel juice may contribute to its carcinogenesis.