Background: Although endoscopic evaluation of the gastrointestinal tract is commonly performed to evaluate iron deficiency, little data is available regarding the underlying causes, yield of evaluation, and long-term outcome for those in whom gastrointestinal and systemic symptoms and signs are absent. Methods: In- or out-patients seen by the gastroenterology consultative service at a large inner-city hospital over a 56-month period were considered eligible for the study when iron deficiency (serum ferritin < 50 ng/mL) was documented. Exclusion criteria included: any gastrointestinal or systemic symptoms/signs, radiographic or endoscopic examinations of the gastrointestinal tract within 3 and 5 years, respectively, or obvious source of blood loss. Patients underwent colonoscopy and if no lesions other than carcinoma were found, upper endoscopy was then performed with a pediatric colonoscope. Results: Fifty-two patients were evaluated (mean age, 66 ± 13 years; range, 20 to 89 years; 32 men/20 women). At the time of evaluation, the mean (±SD) hematocrit was 25% ± 7% (range, 14% to 42%). Overall, 23 patients (44%; 95% Cl 30% to 59%) had an identifiable gastrointestinal lesion considered the cause of iron deficiency, including: colonic carcinoma, 11 (21%); colonic and/or esophagogastric/duodenal vascular ectasias, 9 (17%); and gastric carcinoma, colonic polyposis, and colonic ulcers in 1 patient each. Long-term follow-up (median 24 months, range 2 to 63 months) identified only 1 patient with a cause found (colonic carcinoma), and in this patient, complete colonoscopy was not technically possible at the time of initial evaluation. There were no clinical or laboratory features that distinguished patients with an etiology for iron deficiency to the idiopathic group. Conclusions: Approximately half of patients with iron deficiency in whom gastrointestinal or systemic signs or symptoms are absent have an underlying gastrointestinal lesion. Nevertheless, despite a thorough endoscopic evaluation, some patients will have no etiology found; the prognosis for these patients is excellent.