Epidermolysis bullosa letalis (EBL), an autosomal recessive disorder, is usually fatal in early infancy. Patients surviving the neonatal period generally have a moderate to severe refractory anemia, the pathogenesis of which has never been clarified. Hematological studies were performed in two brothers, ages 12 and 13, with documented EBL. Results included low normal erythrocyte survivals, accelerated plasma iron clearance, mildly decreased erythrocyte iron utilization, and increased plasma iron turnover. Absorption of orally administered iron was demonstrated in both patients. Our findings support the belief that the anemia cannot be attributed to a single mechanism, but represents the anemia of chronic inflammation and infection complicated by iron and protein loss via the skin. Therapy for the anemia must include not only replacement iron in large doses, but also meticulous skin care.