Agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In contrast, the effect of PPARdelta (PPARdelta) agonists in EAE is not yet known. We show that oral administration of the selective PPARdelta agonist GW0742 reduced clinical symptoms in C57BL/6 mice that had been immunized with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide. In contrast to previous results with PPARgamma agonists, GW0742 only modestly attenuated clinical symptoms when the drug was provided simultaneously with immunization, but a greater reduction was observed if administered during disease progression. Reduced clinical symptoms were accompanied by a reduction in the appearance of new cortical lesions, however cerebellar lesion load was not reduced. Treatment of T-cells with GW0742 either in vivo or in vitro did not reduce IFNgamma production; however GW0742 reduced astroglial and microglial inflammatory activation and IL-1beta levels in EAE brain. RTPCR analysis showed that GW0742 increased expression of some myelin genes. These data demonstrate that PPARdelta agonists, like other PPAR ligands, can exert protective actions in an autoimmune model of demyelinating disease.