It is generally assumed that IFNγ plays a central role in acute allograft rejection. To test this hypothesis, we transplanted fully allogeneic (MHC class I and II incompatible) C3H/HeJ (H2 k) murine hearts to IFNγ-/-(IFNγ gene-knockout) and IFNγ+/+ BALB/c (H2 d) mice. The phenotype of IFNγ-/-mice was confirmed by demonstrating absent IFNγ protein production by Con A stimulated IFNγ-/-splenocytes. Both IFNγ-/-and IFNγ+/+ strains rejected transplanted hearts acutely: graft survival (mean±SD) was 5.2±0.4 and 6.0±0.0 days, respectively. Histologic examination revealed similar patterns of acute cellular rejection in both mouse groups. IFNγ mRNA was present in hearts rejected by IFNγ+/+ mice but was absent in those rejected by IFNγ-/-mice. IL-2, IL-4, IL-10, and TNFα mRNA expression, on the other hand, was similar in grafts rejected by either strain. We also observed that hapten-induced delayed-type hypersensitivity (DTH) response was significantly reduced but not absent in IFNγ-/-mice. Our results demonstrate that IFNγ is not required for acute cellular rejection of fully allogeneic murine hearts. We propose that non-DTH mechanisms of allograft destruction could be enhanced in the absence of IFNγ and thus lead to robust acute rejection.