The macrophage activation syndrome (MAS) is a rare, potentially fatal, clinical syndrome, which has been described in childhood rheumatic disorders. MAS is defined by a prolonged period of fevers, pancytopenia, and hypertriglyceridemia (with or without hypofibrinogenemia). Histopathological examination of bone marrow, spleen, or lymph nodes shows hemophagocytosis by mononuclear phagocytes. In patients with Still’s disease, observed triggering events for MAS have included both infectious processes and pharmacological agents, such as parenteral gold and nonsteroidal anti-inflammatory drugs. We report the case of a young woman with adult-onset Still’s disease (AOSD), complicated by an Epstein-Barr virus infection and subsequent MAS, whose course worsened after administration of the soluble tumor necrosis factor-&agr; receptor, etanercept. Subsequent treatment with pulse corticosteroids and cyclosporine A induced a dramatic clinical improvement. Treatment data regarding the use of etanercept in AOSD are lacking; given our experience and recent reports in children with Still’s disease, we would suggest caution using this agent in patients with AOSD, particularly when complicated by MAS.