Mind bomb 1 (Mib1) is a multidomain E3 ligase that directs ubiquitination of the Notch ligands Delta and Jagged to promote their endocytosis. Here we examine Notch-independent functions of Mib1 and find that its activities are linked to the initiation of the extrinsic cell death pathway. Expression of Mib1 induces a spontaneous, caspase-dependent cell death. Consistent with this, depletion of endogenous Mib1 decreases tumor-necrosis factor (TNF)-induced cell death. Mib1 was found to bind to cellular Fas-associated death domain (FADD)-like IL-1b converting enzyme (FLICE)-like inhibitory proteins (cFLIP-L and cFLIP-S), whereas only cFLIP-s can inhibit Mib1-induced cell death. The interaction between Mib1 and cFLIP decreases the association of caspase-8 with cFLIP, which activates caspase-8 and induces cell death. Collectively, these results suggest that in addition to a central role in Notch signaling, Mib1 has an important role in regulating the extrinsic cell death pathway.