Synopsis/Abstract Iron Deficiency (ID) and Iron Deficiency Anemia (IDA) are common in older breastfed infants and toddlers. Treatment of 3-6 mg iron/kg/day is recommended by the American Academy of Pediatrics (AAP), but this regimen often results in only modest changes in iron status, despite being a substantially higher dose (relative to body weight) than is commonly used for adults. We propose that high therapeutic doses of iron induce an inflammatory response, thus increasing hepatic synthesis of a critical regulator of iron absorption, hepcidin, which functions to limit iron absorption in the context of inflammation. In infants and toddlers found to have ID or IDA, we propose to evaluate the efficacy of the addition of Vitamin E to iron therapy compared with the same dose of iron alone. Our primary hypothesis is that in infants and toddlers with ID or IDA, 2 months of supplemental Vitamin E combined with therapeutic iron supplementation will be more efficacious than the same dose of iron alone. The study design is a randomized, double blind efficacy trial of 2 months of iron therapy (6 mg/kg/day) with or without Vitamin E (18 mg/day), in infants and toddlers with ID or IDA from 9 to 24 months of age. Primary outcomes include biomarkers of iron status (ferritin, hemoglobin, transferrin saturation, and transferrin receptor); secondary outcomes include biomarkers of inflammation and oxidant stress. Subjects: We will screen older infants (9-12 months of age) who were predominantly breastfed through at least the first 9 months of life, and toddlers (12-24 months of age) who were breastfed and/or who have modest dietary iron intakes. Intervention: Sixty-eight subjects found to have ID or IDA will be consented and randomized to one of the two treatment regimens (34 subjects per group). Liquid supplement preparations of iron (both groups), Vitamin E (test) and placebo (control) will be distributed by the research pharmacy at The Children's Hospital.Children's Hospital Colorado. Outcomes: Biomarkers of iron status, iron homeostasis, oxidant stress, and of systemic and intestinal inflammation will be repeated at the end of the intervention. If the hypotheses are supported, the findings would provide a simple and effective modification to enhance iron therapy, and to improve the balance between adequate iron uptake to meet physiologic needs and excessive iron intake and its potential adverse effects.