Allograft reperfusion induces inflammation that directs the infiltration of memory T cells into the allograft and their activation to express functions mediating graft injury. The role of cardiac allograft IL-1 receptor signaling in the alloimmune response was investigated. Wild type (WT) C57BL/6 (H-2b) or B6.IL1R−/− hearts were transplanted to A/J (H-2a) mice. Compared to WT allografts, IL-1R-/- allografts had marked decreases in memory CD8 T cell and neutrophil, but not CD4 T cell or macrophage, infiltration and expression of genes encoding proinflammatory mediators at early times post-transplant. Recipients of IL-1R−/− allografts also had marked decreases in de novo donor-specific CD8, but not CD4, T cell development to IFN-γ producing cells on day 7 post-transplant. In recipients depleted of CD4 T cells, IL-1R-/- cardiac allografts survived up to 3 weeks longer than WT allografts. Grafts from bone marrow chimeras indicated that the defects in CD8 T cell alloimmunity in IL-1R-/- allograft recipients were due to the absence of IL-1R signaling on allograft non-bone marrow-derived cells. The results indicate that IL-1R signaling on graft parenchymal cells is required at multiple steps during the course of the alloimmune response to cardiac allografts.