It is generally assumed that IFNgamma plays a central role in acute allograft rejection. To test this hypothesis, we transplanted fully allogeneic (MHC class I and II incompatible) C3H/HeJ (H2k) murine hearts to IFNgamma-/- (IFNgamma gene-knockout) and IFNgamma+/+ BALB/c (H2d) mice. The phenotype of IFNgamma-/- mice was confirmed by demonstrating absent IFNgamma protein production by Con A stimulated IFNgamma-/- splenocytes. Both IFNgamma-/- and IFNgamma+/+ 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. IFNgamma mRNA was present in hearts rejected by IFNgamma+/+ mice but was absent in those rejected by IFNgamma-/- mice. IL-2, IL-4, IL-10, and TNFalpha 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 IFNgamma-/- mice. Our results demonstrate that IFNgamma 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 IFNgamma and thus lead to robust acute rejection.