BACKGROUND Macrophage migration inhibitory factor (MIF) is a secreted proinflammatory lymphokine essential for elicitation of delayed-type hypersensitivity (DTH) reactions in vivo. We tested whether MIF blockade-absence affected acute or chronic murine cardiac allograft rejection. METHODS Wild-type (WT) C57BL/6 (B6) mice underwent transplantation with BALB/c hearts with or without blocking anti-MIF antibody, and MIF knockout (KO) B6 mice underwent transplantation with MIF KO BALB/c hearts. Chronic immune injury was induced in WT and KO recipients using donor-specific transfusion and anti-CD40L antibody. RESULTS Unexpectedly, the blockade or genetic absence of MIF did not prolong graft survival even if recipient T-cell cytotoxicity was additionally impaired. The histologic manifestations of acute and chronic immune injury to the allograft were similar between groups. CONCLUSIONS MIF is not required for acute or chronic allograft rejection in mice. The findings raise questions about the role of DTH as an important mediator of cardiac allograft injury.