The (NZB×NZW)F¹ hybrid mouse develops a severe autoimmune disease similar to systemic lupus erythematosus in humans. Both the human and murine form of the disease show strong associations with alleles of the major histocompatibility complex (MHC) gene products^1,2. The severe form of the disease found in F₁ mice is due, in part, to dominant NZW gene(s) mapping with the H-2 complex (the murine MHC). Here we present evidence that the tumour necrosis factor (TNF-α)gene, which is located within the H-2 complex (the murine major histocompatibility complex), could be involved in the pathogenesis of lupus nephritis in F₁ mice. Thus, a restriction fragment length polymorphism in the TNF-α gene correlates with the reduced levels of TNF-α produced by NZW mice. Furthermore, replacement therapy with recombinant TNF-α induces a significant delay in the development of the nephritis.