Rates of esophageal adenocarcinoma and gastric cardia adenocarcinoma have increased, while rates of esophageal squamous cell carcinoma (ESCC) and gastric noncardia adenocarcinoma have decreased, suggesting distinct etiologies. The authors prospectively investigated the associations of alcohol and tobacco with these cancers in 474,606 US participants using Cox models adjusted for potential confounders. Between 1995/1996 and 2000, 97 incident cases of ESCC, 205 of esophageal adenocarcinoma, 188 of gastric cardia, and 187 of gastric noncardia cancer occurred. Compared with nonsmokers, current smokers were at increased risk for ESCC (hazard ratio (HR) = 9.27, 95% confidence interval (CI): 4.04, 21.29), esophageal adenocarcinoma (HR = 3.70, 95% CI: 2.20, 6.22), gastric cardia (HR = 2.86, 95% CI: 1.73, 4.70), and gastric noncardia (HR = 2.04, 95% CI: 1.32, 3.16). Assuming causality, ever smoking had population attributable risks of 77% (95% CI: 0.55, 0.89) for ESCC, 58% (95% CI: 0.38, 0.72) for esophageal adenocarcinoma, 47% (95% CI: 0.27, 0.63) for gastric cardia, and 19% (95% CI: 0.00, 0.37) for gastric noncardia. For drinkers of more than three alcoholic beverages per day, compared with those whose intake was up to one drink per day, the authors found significant associations between alcohol intake and ESCC risk (HR = 4.93, 95% CI: 2.69, 9.03) but not risk for esophageal, gastric cardia, or gastric noncardia adenocarcinoma.