Autoimmune lupus nephritis is dependent on infiltrating autoreactive leukocytes and Igs. B7 costimulatory molecules (B7-1 and B7-2) provide signals essential for T cell activation and Ig class switching. In MRL- Fas(lpr) mice, a model of human lupus, although multiple tissues are targeted for autoimmune injury, nephritis is fatal. We identified intrarenal B7-1 and B7-2 expression, restricted to kidney-infiltrating leukocytes, before and increasing with progressive nephritis in MRL-Fas(lpr) mice. Thus, we hypothesized that the B7 pathway is required for autoimmune disease in MRL- Fas(lpr) mice. To investigate the role of B7 costimulatory molecules in this autoimmune disease, we generated a MRL-Fas(lpr) strain deficient in B7-1 and B7-2. Strikingly, MRL-Fas(lpr) mice lacking both B7 costimulators do not develop kidney (glomerular, tubular, interstitial, vascular) pathology, or proteinuria, and survive far longer. Intrarenal downstream effector transcripts (IFN-γ IL-12, monocyte chemoattractant protein-1, CSF-1) linked to nephritis remained at normal levels compared with wild-type mice. Skin lesions and lymphoid enlargement characteristic of MRL-Fas(lpr) mice were diminished in B7-1/B7-2-deficient MRL-Fas(lpr) mice. B7-1/B7-2-deficient MRL- Fas(lpr) mice did not develop leukocytic infiltrates, elevated serum IgG and isotypes (G1,G2b,G3), autoantibodies, and intrarenal IgG deposits. Our findings demonstrate that B7-1 and B7-2 costimulatory pathways are critical to the pathogenesis of autoimmune lupus.