The yield of upper endoscopy in asymptomatic patients with positive fecal occult blood test (FOBT) and a negative colonoscopy was evaluated prospectively in 70 consecutive patients. Significant pathology was diagnosed in 19 patients (27%), eight patients with ulcers, five with arteriovenous malformations, three with esophageal or gastric varices, two with multiple erosions, and two with biopsy-proven Barrett's esophagus. Thirteen patients had iron deficiency anemia and demonstrated a 38% prevalence of significant pathology. Fifteen patients on nonsteroidal anti-inflammatory agents had a 30% prevalence of significant pathology. No statistically significant difference was noted between subgroups. In conclusion, asymptomatic patients without a colonic source to explain a positive FOBT often have significant lesions, on upper endoscopy. Iron deficiency anemia did not have an impact on pathology. Because treatment and follow-up plans were altered in many of the cases in which significant pathology was demonstrated, we conclude that upper endoscopy should be seriously considered for all asymptomatic patients with occult gastrointestinal bleeding and a negative colonoscopic examination.