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Purpose: Although in vitro data exist demonstrating an association of Fas and perforin (pfp) with rejecting cardiac allografts, the actual in vivo effector mechanism required for acute rejection is unknown. As the CD4 T-cell is required and sufficient for cardiac allograft rejection, the purpose of this study was to demonstrate the required effector molecule(s) for in vivo CD4 T-cell mediated cardiac allograft rejection. In vitro data strongly suggest a primary role for CD4 T-cell killing via Fas and therefore our hypothesis was that CD4-mediated rejection would require Fas. Procedures: Wild type (Wt) C3H (h-2 k ) and Fas-deficient C3Hlpr (h-2 k ) mice were used as heart donors into immunodeficient Bl/ 6rag Ϫ/Ϫ (h-2 b ) mice reconstituted with naïve Bl/6 CD4 T-cells or naïve Bl/6 pfp Ϫ/Ϫ CD4 T-cells. Mixed lymphocyte reactions were performed with Wt C3H and C3Hlpr gamma-irradiated splenocyte stimulators and Wt Bl/6 or Bl/6 pfp Ϫ/Ϫ CD4 T-cells as responders. Results: Removal of Fas from the donor heart or removal of perforin from the naive CD4 ϩ T-cells did not abrogate rejection individually. In contrast, removal of both donor Fas and CD4 T-cell perforin simultaneously completely abrogated rejection (pϭ0.012 vs C3H ϩ CD4 ϩ