Relapse and remission are characteristics of multiple sclerosis (MS). The underlying mechanisms, however, remain uncertain. Interferon-gamma (IFN-gamma) disturbs the immunological privilege of the central nervous system (CNS) by inducing major histocompatibility complex antigen expression in CNS cells and activating microglia to become antigen-presenting and effector cells. Thus, IFN-gamma and microglia are thought to play important roles in the initiation and development of MS. Here, we show that IFN-gamma induces microglial apoptosis as the activation-induced cell death. This microglial apoptosis was associated with the up-regulation of pro-apoptosis proteins, especially Bax. Microglial apoptosis was also observed in peak EAE mice, but not in early EAE mice. Therefore, IFN-gamma may act on microglia as part of a self-limiting negative feedback system. The activation and subsequent death of microglia induced by IFN-gamma may play pivotal roles in the mechanism of MS relapse and remission.