To study major etiological factors for esophageal cancer in upper gastrointestinal cancer high risk areas in China. Five areas with high incidences of esophageal and gastric cancer with good quality cancer registration data were selected for the study: Cixian, Shexian from Hebei Province, Linxian from Henan Province, Feicheng from Shandong Province and Zhuanghe from Liaoning Province. A total of 250 cases were randomly recruited from the cancer registration database diagnosed as arising in the lower esophageal segment since January 1, 2009. Three controls were identified and matched with each case as having similar characteristics, such as gender, sex and residency. Questionnaires were applied by face to face interview with trained staff, and data entry was conducted using EPIDATA software. Conditional logistic models were employed for univariate and multivariate analyses to evaluate odd ratios and 95% confident intervals, with SPSS 13.0 statistic software. In single variable analysis, gastrointestinal history, GERD, smoking, passive smoking, alcohol drinking, hot food, pickled food, overnight vegetable, dried food, no breakfast, false dining posture were found to be risk factors of esophageal cancer. Eating more fresh vegetables and high BMI were protective factors. Gastrointestinal history (OR=12.658), not taking regular meals (3.465), overnight vegetables (OR=3.296), GERD (OR=3.044), hot food (OR=2.510), passive smoking (OR=2.423), pickled food (OR=2.273), alcohol drinking (OR=2.074), seldom eating breakfast(OR=1.987), and false dining posture (OR=1.977) increased the risk of esophageal cancer on multivariate logistic analysis, and fresh vegetables (OR=0.279) and BMI≥25 (OR=0.528) continued to be protective. Esophageal cancer could be caused by genetics acting in synergy with environmental factors. Health education for the general population in high risk areas should be strengthened, with intervention programs of nutrition and lifestyle focusing on effective prevention and control for upper gastrointestinal cancer.