Endometriosis is characterized by the presence of elevated proinflammatory cytokines such as tumor necrosis factor (TNF) ␣ in the peritoneal cavity. Blocking interaction of TNF␣ with its receptor by the addition of excess TNF␣-binding protein (TBP)-1 (a soluble form of TNF receptor-1) was effective in animal models of endometriosis. Recently, a novel, high-affinity inhibitor of TNF␣, TNF-soluble high-affinity receptor complex (TNF-SHARC), was created by fusing TBP to both the ␣ and ␤ subunits of inactive human chorionic gonadotropin. This dimeric protein was effective in inhibiting collagen-induced arthritis in mice. In the present study, the efficacy of TNF-SHARC in cellular and in vivo models of endometriosis was examined. TBP and TNF-SHARC dose-dependently inhibited TNF␣-induced secretion of interleukin (IL)-6, IL-8, granulocyte macrophage-colony-