Infants of diabetic mothers frequently have polycythemia, elevated serum erythropoietin concentrations, and decreased serum iron and ferritin concentrations, likely representing a redistribution of fetal iron into erythrocytes to support augmented fetal hemoglobin synthesis. We hypothesized that fetal liver, heart, and brain iron concentrations are also reduced in these infants. After obtaining autopsy tissue from infants who had died before 7 days of age, we measured liver, heart, and brain iron concentrations using atomic absorption spectrophotometry. Seven infants of diabetic mothers and seven gestational age-matched control infants were studied. All infants of diabetic mothers had pancreatic islet cell hyperplasia, indicating fetal hyperglycemia and hyperinsulinemia. Liver iron concentrations in the infants of diabetic mothers were 6.6% of control values (489.0±154.4 vs 7379.7±1473.8 μg/gm dry tissue weight (mean±SEM); p<0.001), heart iron concentrations were 43.9% of control values (124.7±20.5 vs 284.1±34.8 μg/gm dry tissue weight; p<0.002), and brain iron concentrations were 60.6% of control values (106.1±13.7 vs 175.2±10.7 μg/gm dry tissue weight; p<0.003). Heart and brain iron concentrations were directly correlated with liver iron concentrations (r=0.80 for both; p<0.001) and indicated that hepatic iron was >75% depleted before heart and brain iron reduction. We conclude that severely affected infants of diabetic mothers have reduced liver, heart, and brain iron concentrations. The role of tissue iron deficiency in the genesis of the abnormal clinical findings in these infants deserves further consideration.