Some mutations in FOXL2 are responsible for premature ovarian failure accompanied with blepharophimosis-ptosis-epicanthusinversus syndrome (BPES) typeI disease, and FOXL2-null mice exhibit developmental defects of granulosa cells. Recently, a new somatic mutation in FOXL2,c.402C>G, leading top. C134W change, has been identified in a vast majority of adult-type ovarian garnulosa cell tumors (GCTs). In the current study, we investigated possible mechanisms by which the C134W mutation could contribute to GCT development. The wild-type (WT) FOXL2 and its mutant form displayed differential apoptotic activities, in which WT induced a significant granulosa cell death while the mutant exhibited a minimal cell death effect. The FOXL2-induced apoptotic response was greatly dependent on caspase8, BID, or BAK since the depletion of either of them prevented FOXL2 to elicitits full apoptotic responses. Stimulated activation of caspase8, consequently resulting increased production of truncated BID (tBID), up-regulation and oligomerization of BAK, and release of cytochromec were all associated with the apoptosis followed by WT FOXL2 expression. In contrast, the mutant FOXL2 was deficient to elicit the full apoptotic signaling responses. In addition, we found the differential up-regulations of expression of death receptors including Fas and TNF-R1 between the WT and the mutant. Moreover, granulosa cells expressing either the WT FOXL2 or its variant form (C134W) exhibited distinct cell death sensitivities by the activation of death receptors. Thus, these differential activities of FOXL2 and it mutant may partly account for the pathophysiology of GCT development occurred by the somatic mutation (C134W) of FOXL2.