Autoimmune disease in MRL-Fas lpr mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-γ-secreting T cells, and 2) MRL-Fas lpr mice deficient in the IFN-γ receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Fas lpr mice reduces IFN-γ-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Fas lpr (IL-12−/−) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12−/− mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4+, CD8+, CD4− CD8− B220+) and macrophages was dramatically reduced in IL-12−/− MRL-Fas lpr kidneys. We determined that there were fewer IFN-γ transcripts (> 70%) in the IL-12−/− protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12−/− MRL-Fas lpr kidneys generated substantially less IFN-γ when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-γ in these IL-12−/− MRL-Fas lpr kidneys. Of note, survival was modestly extended in the IL-12−/− MRL-Fas lpr mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12−/− MRL-Fas lpr mice, renal pathology and IFN-γ expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.