Interleukin-11(IL-11) displays epithelial cytoprotective effects during intestinal injury. Anti-apoptotic effects of IL-11 have been described, yet mechanisms remain unclear. Fas/CD95 death receptor signaling is up-regulated in ulcerative colitis leading to mucosal breakdown. We hypothesized that IL-11 inhibits Fas Ligand(FasL)-mediated apoptosis in intestinal epithelia. Cell death was monitored in IEC-18 cells by microscopy, caspase and PARP cleavage, mitochondrial release of cytochrome c and abundance of cytoplasmic oligonucleosomal DNA. RT-PCR was used to monitor Fas, cIAP1, cIAP2, XIAP, cFLIP, survivin and Bcl2 family members. Fas membrane expression was detected by immunoblot. Inhibitors of JAK2, PI3-Kinase, Akt 1, MEK 1,2 and p38 MAP kinases were used to delineate IL-11's anti-apoptotic mechanisms. IL-11 did not alter Fas expression. Pre-treatment with IL-11 for 24 hours prior to FasL reduced cytoplasmic oligonucleosomal DNA by 63.2%. IL-11 also attenuated caspase-3, 9 and PARP cleavage without affecting expression of activated caspase-8 p20 or cytochrome c release. IL-11 did not affect mRNA expression of the candidate anti-apoptotic genes. The MEK 1,2 inhibitors U0126 and PD98059 significantly attenuated the protection of IL-11 against caspase-3 and -9 cleavage and cytoplasmic oligonucleosomal DNA accumulation. While Akt inhibition reversed IL-11 mediated effects on caspase cleavage, it did not reverse the protective effects of IL-11 by DNA ELISA. We conclude that IL-11-dependent MEK 1, 2 signaling inhibits FasL-induced apoptosis. The lack of reversal of the IL-11 effect on DNA cleavage by Akt inhibition, despite antagonism of caspase cleavage, suggests that IL-11 inhibits caspase-independent cell death signaling by FasL in a MEK-dependent manner.