Using a simple hemagglutination assay to determine A and B blood types, we surveyed 1,072 domestic short- and longhair (DSH/DLH) cats and 1,100 purebred cats in the United States. Data from 234 matings with 552 offspring were consistent with the hypothesis that feline blood types A and B are due to the action of two different alleles at the same gene locus and that A is completely dominant over B. Neither an AB nor an O type cat was encountered. No type B cats were found in the Siamese and related breeds or in American Shorthair and Norwegian Forest cats. Among the breeds with type B blood, the proportion was lowest in DSH/DLH cats (0.0028) and variably higher in Abyssinian, Birman, British Shorthair, Devon Rex, Himalayan, Persian, Scottish Fold, and Somali, ranging from 0.15 to 0.59. Since all type B cats have strong, naturally occurring anti-A alloantibodies, fatal neonatal isoerythrolyses occur in type A offspring of type B mothers bred to type A males. The gene frequency of the B allele and the proportion of mating at risk of neonatal isoerythrolysis were estimated in a number of breeds. In most breeds, the frequency of the B allele was less than 0.5. Since the kittens at risk for neonatal isoerythrolysis always have the genotype AB, there is constant natural selection against heterozygotes. Heterozygote disadvantage in the cat AB system represents an unusual form of negative selection, similar to that in Rh blood group incompatibility in humans.