The role of the interferon-gamma (IFN-gamma) receptor 1 (IFN-gammaR1) was investigated in the regulation of MHC expression in kidney in the basal state, in response to potent inflammatory stimuli, and after renal injury. In this study, MHC regulation in mice lacking IFN-gammaR due to targeted disruption of the IFN-gammaR1 gene (GRKO mice) was compared with regulation in 129Sv/J mice with wild-type IFN-gammaR1 genes. Basal class I expression was reduced by approximately 45% in kidneys of GRKO mice, while basal class II expression was confined to interstitial cells and was not reduced in GRKO kidneys. Recombinant IFN-gamma administration induced widespread expression of class I and II in renal tubules, arterial endothelium, and glomeruli of 129Sv/J mice, but produced no change in kidneys of GRKO mice. Potent systemic inflammatory stimuli (injections of allogeneic cells, skin sensitization with oxazolone, and injection of bacterial lipopolysaccharide) significantly induced both class I and class II expression in 129Sv/J mice, but not in GRKO mice. Acute renal injury increased local expression of class I and II in both 129Sv/J and GRKO mice, but the induction in GRKO mice was reduced compared with 129Sv/J mice. Thus, the IFN-gamma receptor plays a unique and nonredundant role in the regulation of renal MHC in the response to inflammation, in the response to renal injury, and in the basal state.