BACKGROUND: Few studies have investigated the relationship of physical activity to esophageal and gastric carcinoma according to histology and anatomic site. METHODS: This study prospectively investigated the association between physical activity and esophageal and gastric carcinoma in a cohort of 487,732 U.S. men and women, followed from 1995-1996 to December 31, 2003. All analyses were performed in 2007-2008. RESULTS: During 8 years of follow-up study, 523 cases of esophageal carcinoma (149 squamous cell and 374 adenocarcinoma) and 642 cases of gastric carcinoma (313 cardia and 329 noncardia) were documented. Physical activity was associated with reduced risk of esophageal and gastric adenocarcinomas but was unrelated to esophageal squamous cell carcinoma. The inverse association with physical activity was strongest for gastric noncardia adenocarcinoma (multivariate relative risk [RR] for highest versus lowest physical activity level=0.62, 95% CI=0.44, 0.87). Relationships were weaker but evident for gastric cardia adenocarcinoma (RR=0.83; 95% CI=0.58, 1.19) and esophageal adenocarcinoma (RR=0.75; 95% CI=0.53, 1.06). No significant relationship with physical activity was observed for esophageal squamous cell carcinoma (RR=1.05; 95% CI=0.64, 1.74). Exclusion of cases diagnosed during the first 2 follow-up years did not change those estimates, indicating that the findings are not due to decreased activity levels among participants with undiagnosed cancer at entry. CONCLUSIONS: Physical activity may play a role in the prevention of upper gastrointestinal tract adenocarcinomas. No association was seen between physical activity and esophageal squamous cell carcinoma.