Liver X receptors (LXR) form functional heterodimers with the retinoid X receptors (RXR) and regulate cholesterol, lipid and glucose metabolism. We demonstrated previously that activation of LXR modulates insulin secretion in MIN6 cells and pancreatic islets. In this study we investigated the effects of the LXR agonist TO901317 and the RXR agonist 9-cis-retinoic acid (9cRA) on cell proliferation and apoptosis in MIN6 cells. While TO901317 showed no effect on proliferation of MIN6 cells, combination of T0901317 with 9cRA inhibited cell proliferation. Flow cytometry analysis of cell cycle demonstrated that activation of LXR/RXR prevented MIN6 cells from G1 to G2 phase progression. Combination of T0901317 and 9cRA increased apoptosis rate and caspase 3/7 activity in MIN6 cells. Moreover, T0901317 or its combination with 9cRA significantly increased the cell susceptibility to free fatty acid- and cytokine-induced apoptosis. Treatment of MIN6 cells with LXR and RXR agonists produced a strong increase in expression of Smad3, a protein known to inhibit cell cycle G1/S phase progression and to induce apoptosis. In isolated rat islets the effect of palmitic acid on caspase 3/7 activity was increased with T0901317 alone and even more with the combination of TO901317 and 9cRA. Thus, activation of LXR/RXR signaling inhibits cell proliferation and induces apoptosis in pancreatic -cells.