During inflammatory reactions in the central nervous system (CNS), resident macrophages, the microglia, are exposed to Th1 cell‐derived cytokines and pro‐apoptotic Fas ligand (FasL). Despite the presence of TNF‐α and IFN‐γ, both being capable of sensitzing microglia to FasL, apoptosis of microglia is not a hallmark of inflammatory diseases of the CNS. In the present study, TGF‐β is found to counteract the effect of TNF‐α and IFN‐γ to sensitize microglia to FasL‐mediated apoptosis. Resistance to Fas‐mediated apoptosis by TGF‐β does not correlate with a down‐regulation of Fas expression. As a key inhibitor of Fas‐mediated apoptosis, we found expression of the cellular FLICE‐inhibitory protein (c‐FLIP) to be induced by TGF‐β in resting as well as in activated microglia. Induction of FLIP was found to depend on a mitogen‐activated protein kinase kinase (MKK)‐dependent pathway as shown by the use of the specific MKK‐inhibitor PD98059. The presence of FLIP strongly interfered with FasL‐induced activation of caspase‐8 and caspase‐3 preventing subsequent cell death. The presented data provide the first evidence for a TGF‐β‐mediated FLIP in macrophage‐like cells and suggest a mode of action for the anti‐apoptotic role of TGF‐β in the CNS.