Cisplatin is a chemotherapeutic agent that induces tumor necrosis factor-α (TNF-α) production in many cell types with unfortunate renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrow-derived immune cells to the pathogenesis of cisplatin-induced renal injury in vivo. To do this we created chimeric mice in which the bone marrow was ablated and replaced with donor bone marrow cells from wild-type or from TNF-α knockout mice. Six weeks after reconstitution, the chimeric mice were treated with cisplatin and renal structural and functional parameters were measured. Chimeras with kidneys of wild-type animals all developed significant renal failure after 72 h of cisplatin treatment regardless of the immune cell source. Chimeras with kidneys of TNF-α knockout mice showed significantly less renal dysfunction (blood urea nitrogen, serum creatinine, and glomerular filtration rate), renal histologic injury, and serum TNF-α levels; again regardless of the immune cell source. Urinary excretion of several proinflammatory cytokines was lower in the wild-type bone marrow-knockout kidney chimera mouse than in wild-type background mice. Our results indicate that a substantial portion of circulating and urinary TNF-α is derived from nonimmune cells after cisplatin administration. We conclude that the production of TNF-α by renal parenchymal cells, rather than by bone marrow-derived infiltrating immune cells, is responsible for cisplatin-induced nephrotoxicity.