Summary: Runt disease was produced in newborn mice of certain inbred strains and their hybrids by the intraperitoneal injection of various organ and tissue preparations rich in viable lymphoid cells. The incidence of runting among mice of various inbred strain donor-recipient combinations was found to differ markedly and was highest in mice of those combinations differing at the H-2 locus. Among mice of combinations compatible at the H-2 locus but differing at other loci, runting could be produced only by immunization of the donors prior to cell transfer. In certain donor-recipient combinations of inbred strains and their hybrids the incidence of runting produced in the hybrid was inversely proportional to the degree of “foreignness” of the hybrid for the donor's cells. In certain strain combinations, the susceptibility of hybrid mice to runting with the cells of one parent was greater than with the cells of the other parent. Induction of immunological tolerance in newborn mice of parent strains with the cells of their respective hybrids markedly increased their susceptibility to subsequent runting with spleen cells of the homologous parent. Contrariwise, the spleen cells of such “tolerant” donors had a lowered capacity to produce runt disease in hybrid mice or mice of the homologous parent strain. When immune peritoneal cells from C57BL/K mice, which had recently rejected Sarcoma I ascites tumor, were injected into 5-day-old A/Jax mice, they produced an acute form of homologous disease terminating in death within 5 days. Immune spleen cells from the same animals produced a more chronic form of the disease, terminating in death in 3 to 5 weeks. Whereas immune spleen cells from A/Jax mice produced a “chronic” form of homologous disease in adult (C57BL/K × A/Jax) hybrid mice, immune spleen cells from C57BL/K mice failed to produce homologous disease in the adult hybrid. A mild form of runt disease was produced in newborn male mice of the C57BL/K and A/Jax strains with immune spleen cells obtained from isologous adult female mice that had recently rejected skin grafts from male mice of the same strain. Attempts to serially transfer runt disease in newborn A/Jax and (C57BL/K × A/Jax) hybrid mice with large doses of spleen cells were not successful beyond the first or second passage. The significance of the results is discussed.