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Abstract Background Normal upper endoscopy may be a marker of ischemic heart disease in patients with unexplained chest/epigastric pain. Methods We examined the 10-year risk of ischemic heart disease and mortality in a cohort of 386 Danish patients with chest/epigastric pain, normal upper endoscopy, and no prior hospital discharge diagnosis of ischemic heart disease (defined as patients with unexplained chest/epigastric pain), compared with 3,793 population controls matched by age, gender, and residence. Outcome data were obtained from population-based health registries. Cox regression analysis was used to estimate the relative risk of hospitalization for ischemic heart disease and the adjusted mortality rate ratio (MRR). Results The 10-year relative risk of hospitalization for ischemic heart disease following a normal upper endoscopy among patients with unexplained chest/epigastric pain was 1.6 (95% CI, 1.1–2.2), compared with controls. The 10-year MRR was 1.1 (95% CI, 0.9–1.5). Within the first year after the upper endoscopy the MRR was 2.4 (95% CI, 1.3–4.5). The cause-specific MRR among patients with unexplained chest/epigastric pain compared with controls was up to threefold higher for deaths related to alcohol dependence, pneumonia, and lung cancer. Conclusion Unexplained chest/epigastric pain in patients with normal endoscopy is a strong marker for ischemic heart disease and increased mortality.