OBJECTIVE: To determine the clinical outcome of a cohort of patients over the age of 50 yr with iron deficiency anemia in whom a source was not identified during a prior GI evaluation. METHODS: A cohort of 69 patients (43 men, 26 women) with a mean age of 68 yr (range 50-89 yr) who previously had a negative GI evaluation for documented iron deficiency anemia was followed for an average of 39 months (range 2-89 months). RESULTS: In 49 patients (71%), the iron deficiency anemia resolved. All remained stable during the follow-up period except five patients in whom iron deficiency recurred (from 18 months to 5 yr later). Subsequent GI evaluations were negative, and iron deficiency resolved with iron supplementation in all five patients. In 16 patients (23%), a mild chronic anemia persisted during the follow-up period. None of these patients required transfusions, and 12 of the 16 had concomitant medical illnesses that likely contributed to an anemia of chronic disease. Only four patients (6%) had a persistent anemia severe enough to require intermittent transfusions. However, in three of these patients, the anemia was likely secondary to chronic disease (chronic renal failure in two patients, metastatic carcinoma in one patient). Therefore, only one patient (1%) had consistent iron deficiency anemia severe enough to require intermittent transfusions, which was found to be secondary to duodenal angiodysplasia during a subsequent GI evaluation. CONCLUSION: The prognosis of iron deficiency anemia in older patients after a negative GI evaluation is favorable. The anemia resolves and remains stable in the majority of patients after iron replacement. Subsequent GI evaluations should be reserved for those patients whose anemia is refractory to iron replacement and in whom there are not concomitant medical illnesses contributing to an anemia of chronic disease.