This study examines the effects of environmental hazards, including tobacco, alcohol/alcohol flush response, areca nut, and Helicobacter pylori (H pylori) infection on upper digestive diseases. This is a multi-hospital-based endoscopy-survey cross-sectional study. Subjects were received upper endoscopies in outpatient clinics at four hospitals in Taiwan between 2008 and 2013. Biopsy-based methods or urea breath test were used confirm the status of H pylori infection. In total, 8135 subjects were analyzed. Higher cumulative amounts of alcohol consumption were at higher risk of Barrett's esophagus and esophageal squamous cell carcinoma (ESCC), higher cumulative amounts of tobacco consumption were at higher risk of peptic ulcer, and higher cumulative amounts of areca nut consumption were at higher risk of duodenitis. Alcohol flush response was significant risk for reflux esophagitis and Barrett's esophagus (adjusted odds ratio [aOR] = 1.18 and 1.32, 95% confidence interval [CI] = 1.07-1.31 and 1.06-1.65, respectively). H pylori infection was inversely associated with ESCC risk (aOR = 0.20, 95% CI = 0.10-0.40). In addition, H pylori infection was consistently and significantly risk factors for gastrointestinal diseases, including peptic ulcer, gastric adenocarcinoma, and duodenitis (aOR = 5.51, 1.84, and 2.10, 95% CI = 4.85-6.26, 1.03-3.26, and 1.71-2.56, respectively). Besides the cumulative risk of alcohol, tobacco, and areca nut for Barrett's esophagus, ESCC, and peptic ulcer, respectively, presence of facial flushing was the significant risk for reflux esophagitis and Barrett's esophagus. H pylori infection was positively associated with peptic ulcer, gastric adenocarcinoma, and duodenitis, but inversely associated with ESCC.