INTRODUCTION: Despite undergoing standard endoscopic diagnostic evaluation with eosophagogastroduodenoscopy and ileocolonoscopy, up to 30% of patients with iron deficiency anemia (IDA) have no definitive diagnosis. The aim of this study was to prospectively investigate the role of wireless capsule endoscopy (WCE) in detecting lesions of the small bowel in patients with unexplained IDA after a negative endoscopic work-up. PATIENTS AND METHODS: Between 1 December 2003 and 31 December 2004, 253 consecutive patients who had been referred because of unexplained IDA underwent eosophagogastroduodenoscopy with small-bowel biopsies and ileocolonoscopy. Endoscopic and histological investigations were negative in 51 of these patients (20.2%) and WCE was performed. Air double-contrast enteroclysis was performed following WCE in all these patients. RESULTS: Wireless capsule endoscopy revealed one or more small-bowel lesions that were considered to be a likely cause of the IDA in 29/51 patients (57%): angiodysplasias in twelve patients (23.5%), multiple jejunal and/or ileal ulcers in six patients (11.7%), multiple erosions in four patients (7.8%), a solitary ulcer in three patients (5.9%), polyps in two patients (3.9%), and tumors in two patients (3.9%). Enteroclysis revealed abnormal findings likely to cause IDA in only 6/51 patients (11.8%): multiple ileal ulcers in three patients (5.9%), tumors in two patients (3.9%), and polyps in one patient (1.9%) (enteroclysis VS. WCE, P < 0.0001). WCE revealed all of the radiographic findings and no adverse events were observed. CONCLUSIONS: This study demonstrates the importance of investigating the small bowel with WCE in patients with unexplained IDA after negative standard endoscopic evaluation. Wireless capsule endoscopy is superior to enteroclysis for detecting lesions of the small bowel in patients with unexplained IDA and should be the next diagnostic test of choice after unremarkable standard endoscopic evaluation.