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Mouse hearts were transplanted heterotopically as primarily vascularized grafts. Donors and recipients were selected to provide combinations in which there was histoincompatibility with respect to antigens whose specificities are determined by genes at the H-2D region only (B10.BR → B6AF1), at the H-2K region only (B10.D2 → B6AF1), at loci other than H-2 (129 → B/10); and at H-2D, H-2K, and non-H-2 loci (A → (129 X B/10)F1). In all of these combinations there were acute episodes of rejection as indicated by sharp declines in palpable impulse. Return of cardiac impulse was commonly observed after this initial decline but was short lived except in the case of B10.BR grafts in B6AF1 hosts. In that combination all of the grafted hearts showed at least partial recovery and long-term survival. Hearts appear to be more vulnerable than kidneys but less vulnerable than skin to allograft reactions. In the combinationss studied there was a close relationship between the survival times of allografts of hearts and skin. Both types of grafts underwent relatively early and acute rejection in situations involving only non-H-2 differences and they had similar degrees of prolongation in survival time when placed on mice treated with antiserum specifically reactive with graft antigens. Differential survival of allografts of various kinds is ascribed to both differences in the intensity of the immune responses that are provoked and differences in sensitivity to attack by immune substances.