Objective. To determine the effects of anti-tumor necrosis factor (anti- TNF) therapy in the inflammatory and autoimmune disease in motheaten (me/me) mice, which exhibit a Fas apoptosis signaling defect. Methods. Arthritis, pneumonitis, and mortality were analyzed in me/me mice treated with a novel, soluble, dimeric TNF receptor I (sTNFRI) molecule capable of high-affinity binding and neutralization of TNFα. Results. Soluble TNFRI reduced serum levels of TNFα and led to a 2-fold increase in the lifespan of me/me mice, compared with the control treatment group. The treatment also reduced the development of the 'motheaten' skin patches and alleviated pneumonitis and inflammatory lesions in the extremities of me/me mice compared with controls. However, the serum levels of IgM and IgM anti-double-stranded DNA autoantibody were comparable to those of untreated control mice. Conclusion. TNFα is an important cytokine involved in the pathogenesis of inflammatory disease in me/me mice, resulting in tissue damage and early mortality. Therapies directed at blocking TNF/TNFR interactions, such as the sTNFRI used in these experiments, may be effective in diseases associated with apoptosis defects leading to overutilization of the TNF/TNFR pathway.