SUMMARY Twenty-four hours after receiving 300 or 500 R of X-irradiation, F1 hybrid mice were injected with parental strain lymphoid cells in order to cause a graft-versus-host reaction. Spleen index values obtained from these mice 8 days after thymus cell injection were increased (300 R) or decreased (500 R) in comparison to the values obtained from unirradiated hosts. Hosts X-irradiated with 500 R and injected with parental strain spleen or thymus cells showed decreased spleen index values, in comparison to controls receiving irradiation only, or irradiation and hybrid cells. X-irradiation with 500 R therefore abolishes the usual host proliferative response of splenomegaly. In spite of the absence of splenomegaly, the 500 R X-irradiated hosts developed graft- versus-host disease earlier than the 300 R X-irradiated hosts in which splenomegaly was present. It is concluded that host proliferative responses such as splenomegaly play no essential role in the pathogenesis of graft-versus-host disease.