Background: Epithelial cell death and compromised barrier function are key features of inflammatory bowel disease (IBD) pathogenesis. Previous studies suggest the nuclear bile acid receptor, farnesoid X receptor (FXR), to promote intestinal barrier function and protect against inflammation. Here, we investigated potential mechanisms involved. Methods: T(84) cell monolayers were treated with a combination of IFNgamma and TNFalpha to model cytokine-induced barrier dysfunction in vitro. Apoptosis and necroptosis were assessed by measuring caspase 3/PARP cleavage and RIP3 phosphorylation, respectively. Epithelial permeability was determined by measuring 4 kDa FITC-dextran (FD4) flux. Effects of FXR on barrier function in DSS-treated mice were assessed by measuring plasma levels of orally-administered FD4. Results: Treatment with IFNgamma and TNFalpha enhanced FD4 flux and increased apoptosis in T84 monolayers, as evidenced by increased cleaved PARP and caspase 3 levels. Pre-treatment with the FXR agonist, GW4064, significantly inhibited cytokine-induced FD4 flux, but not apoptosis. Treatment with IFNgamma and TNFalpha in the presence of the apoptosis inhibitor, Q-VD-OPh, induced necroptosis, as evidenced by increased RIP3 phosphorylation, and enhanced FD4 flux, whereas a necroptosis inhibitor, necrostatin, inhibited these effects. GW4064 also inhibited cytokine-induced RIP3 phosphorylation and FD4 flux in the presence of Q-VD-OPh. In mice, treatment with the FXR agonist, obeticholic acid, attenuated DSS-induced disease activity and mucosal FD4 flux, but not levels of cleaved caspase 3 or pRIP3. Conclusion: FXR activation inhibits cytokine-induced barrier dysfunction by inhibiting epithelial necroptosis rather than apoptosis in vitro. How such effects contribute to protective actions of FXR in vivo require further elucidation.