Severe gastrointestinal necrosis and strictures after an iron overdose are well described. However, mucosal injury in patients receiving therapeutic iron has received only scant recognition despite its wide use. We studied the clinical and histologic features of 36 upper gastrointestinal tract biopsies from 33 patients (24 gastric, 9 esophageal, 1 gastroesophageal junction, and 2 duodenal) containing characteristic brown crystalline iron material, and evaluated the amount and tissue distribution of the iron. In addition, we investigated the prevalence of iron-associated mucosal injury in upper gastrointestinal endoscopic examinations. The majority of the biopsies (32 of 36, 89%) contained luminal crystalline iron adjacent to the surface epithelium or admixed with luminal fibrinoinflammatory exudate. Thirty biopsies (83%) showed crystalline iron deposition in the lamina propria, either covered by an intact epithelium, subjacent to small superficial erosions, or admixed with granulation tissue. Three biopsies (8%) demonstrated iron-containing thrombi in mucosal blood vessels. Erosive or ulcerative mucosal injury was present in 30 of 36 biopsies (83%). The amount of iron accumulation in cases with mucosal injury was greater than in cases without mucosal injury (mean grades, 2.4+ vs. 1.3+ on a 1+ to 3+ scale; p = 0.002). Iron medication was confirmed in 25 of 33 patients (76%) 22 patients were receiving ferrous sulfate. Approximately half of the patients (17 of 33, 51%) also had underlying infectious, mechanical, toxic, or systemic medical conditions that could have initiated or exacerbated tissue injury. Crystalline iron deposition was found in 0.9% of upper gastrointestinal endoscopic examinations (12 of 1,300), and iron medication-associated erosive mucosal injury was present in 0.7% (9 of 1,300). These results indicate that crystalline iron deposition in the upper gastrointestinal tract is not uncommon. It can induce or exacerbate a distinctive histologic pattern of erosive mucosal injury, especially in patients with associated upper gastrointestinal disorders. Recognition of this pattern by pathologists and its communication to clinicians may aid in optimizing therapy.