Monocytes and macrophages have long been associated with acute and chronic allograft rejection; this is mediated by their abilities to promote inflammation, kill target cells via antibody-dependent cytotoxicity and modulate adaptive immunity. Our present study showed that allogeneic antigen-primed macrophages acutely rejected skin grafts with specificity after adoptive transfer into MHC-matched immunodeficient mice. The ability of primed macrophages to reject allografts essentially requires the help of CD4⁺ T cells and does not require the help of CD8⁺ T cells. Moreover, the primed, perforin-deficient macrophages rejected the skin grafts in a significantly delayed pattern compared with WT macrophages, indicating that the perforin pathway of the primed macrophages is likely involved in the rejection process. Thus, primed macrophages are endowed with adaptive immunity-like features, such as specificity, with the help of CD4⁺ T cells during the immune response to allografts. The present study challenges our traditional views of macrophage functions and highlights the biological functions of macrophages beyond innate immunity in mammals.