Four hundred and ten heterotopic spleen transplants were performed in inbred guinea pigs of strains 2 and 13 whose major histocompatibility complex differs only in the I region and which rapidly reject reciprocal skin allografts. Spleen allografts from strain 13 to strain 2 survived throughout the lifetime of the hosts, whereas spleen allografts from strain 2 to strain 13 were rejected within 3 weeks. Animals not rejecting their spleen transplants were specifically tolerant of donor strain skin allografts. Strain 2 recipients of strain 13 spleen grafts had a surprising high mortality from graft-versus-host disease which peaked at 6 weeks after transplantation.