CSF-1 and TNF-α in the kidney of MRL-Fas lpr mice are proximal events that precede and promote autoimmune lupus nephritis, while apoptosis of renal parenchymal cells is a feature of advanced human lupus nephritis. In the MRL-Fas lpr kidney, infiltrating T cells that secrete IFN-γ are a hallmark of disease. To examine the impact of IFN-γ on renal injury in MRL-Fas lpr mice, we constructed a IFN-γR-deficient strain. In MRL-Fas lpr mice lacking IFN-γR, circulating and intrarenal CSF-1 were absent, TNF-α was markedly reduced, survival was extended, lymphadenopathy and splenomegaly were prevented, and the kidneys remained protected from destruction. Mesangial cells (MC) that were signaled through the IFN-γR induced CSF-1 and TNF-α in MRL-Fas lpr mice. We detected a large number of apoptotic renal parenchymal cells in advanced nephritis and determined that signaling via the IFN-γR induces apoptosis of tubular epithelial cells (TEC), but not MC. By comparison, TNF-α induces apoptosis in MC, but not TEC, of the MRL-Fas lpr strain. Thus, IFN-γ is directly and indirectly responsible for apoptosis of TEC and MC in MRL-Fas lpr mice, respectively. In conclusion, IFN-γR signaling is essential for the initiation (CSF-1), acceleration (CSF-1 and TNF-α), and apoptotic destruction of renal parenchymal cells in MRL-Fas lpr autoimmune kidney disease.