Gastrointestinal (GI) complaints are among the most common symptoms in primary care yet are frequently unexplained and often lead to costly diagnostic testing. We sought to determine the prevalence of psychiatric disorders in patients with unexplained GI complaints undergoing upper endoscopy, and the likelihood of endoscopic abnormalities in patients with and without psychiatric diagnoses. We prospectively evaluated 116 adult patients who were undergoing upper endoscopy to evaluate GI complaints. All subjects received a structured psychiatric interview prior to endoscopy using PRIME-MD, and endoscopists were blinded to the PRIME-MD results. Psychiatric disorders were detected in 70 (60%) patients. Overall, there were 113 diagnoses (some patients had multiple disorders) with the most common being somatoform (44%), depressive (29%), and anxiety (19%) disorders. Only 29 patients had major endoscopic abnormalities, including esophageal disease (14), peptic ulcer (9), severe gastritis (4), gastric cancer (1), and esophageal cancer (1). There was a much higher prevalence of psychiatric disorders in patients without major endoscopic abnormalities (74% vs. 21%, p < 0.0001). Psychiatric disease was strongly predictive of endoscopic findings (OR for major abnormality = 0.11 in women, and 0.40 in men), especially if somatoform disorder was present (OR = 0.15). We conclude that, with a simple questionnaire, psychiatric disorders can be diagnosed in a large proportion of patients with unexplained GI complaints who are referred for upper endoscopy. The presence of a psychiatric disorder, particularly if somatoform, makes it unlikely that endoscopy will reveal significant GI disease.