Isophilic immune response was profoundly depressed in rats injected with heterophilic antigen during the first week of life and challenged with sheep red cells 10 to 18 weeks later. Untreated litter mates served as controls. When neonatal treatment was given during the second week of life and/or challenge with sheep red cells was deferred until 20 weeks, the isophilic immune response was inhibited to a lesser degree. Rats injected neonatally with sheep red cells had decreased amounts of isophilic and heterophilic antibodies upon challenge with sheep red cells 12 weeks later, while intervals of 16 to 20 weeks between neonatal treatment and adult immunization with sheep red cells increased heterophilic antibodies without significant changes in isophilic antibodies. Rats exposed neonatally to either heterophilic antigen or sheep red cells, and challenged with heterophilic antigen as adults, formed significantly more heterophilic antibodies than did control litter mates. These observations were interpreted as resulting from imprinting of large numbers of cells with receptors for heterophilic antigen after neonatal exposure to the antigen, and cellular diversion of antigen upon challenge of adult animals with sheep red cells. The possible relationship of this phenomenon to the interference with Rh immunization of ABO incompatibility in man was considered.