Previous studies suggest that race is a risk factor in ABO hemolytic disease of the newborn (ABO-HDN). In order to compare the prevalence of ABO-HDN in Asian, Black, Hispanic and Caucasian infants, we studied 10,611 consecutive births at one hospital over a 6-year period. Among group A infants born to group O mothers, the prevalence of positive DAT differed among the four groups (p = 0.007), and was highest in Asians (50%) and lowest in Caucasians (31%). However, the proportions of infants who required exchange transfusion were not different (p = 0.351). Among group B infants born to group O mothers, the prevalence of positive DAT was not different among the four groups (p = 0.26) and none of these 166 group B infants with a positive DAT result required exchange transfusion. Our findings suggest that there are small ethnic differences in the prevalence of positive DAT results in group A infants born to group O mothers, but the prevalence of clinical disease which requires exchange transfusion does not differ significantly among Asian, Black, Hispanic and Caucasian infants.