AbstractData from the period 1951 to 1967 were collected from the records at the Milwaukee Blood Center on 380 cases of ABO hemolytic disease to determine if ABO incompatibility may be regarded as a selection mechanism at the ABO locus. In comparison with infants of ABO compatible parents the affected infants had significantly lower hemoglobin and hematocrit values and higher bilirubin concentrations. Forty‐eight percent of the affected showed a positive direct antiglobulin test, 81% showed increased numbers of reticulocytes and 92% had spherocytosis. Since affected infants are considered to be in grave danger when high concentrations of bilirubin are present it is significant that 169 individuals (44%) required exchange transfusions. Compared with the number of live births in Milwaukee for the same period this represents a frequency of one in every 1,654 live births so that ABO incompatibility may be regarded as an important mechanism of natural selection. Since it was found that 98.7% of the mothers of the affected infants are of blood group O, the affected infants are therefore heterozygous (AO or BO) and selection due to ABO incompatibility would have its greatest effect upon the lowest allele frequencies in a population.