Two siblings born 6 years apart presented with similar findings of hepatosplenomegaly, dermal hematopoiesis, hemoglobinuria, and increased platelet consumption, but only moderate anemia and normal serum bilirubin. ABO incompatibility was identified, and other causes were excluded. A review of the current understanding of mechanisms that promote and prevent antibody-mediated hemolysis in the fetus is reviewed. Due to the low ratio of observed to expected significant clinical events among ABO incompatible mother-infant pairs, and the multiplicity of mechanisms that diminish hemolysis, we speculate that severe ABO hemolytic disease of the newborn occurs when there is a specific failure in one of these preventive mechanisms.