PPARs belong to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation. A crucial role both for PPARgamma and for PPARalpha for the regulation of autoimmunity has been clearly demonstrated, as receptor agonists had beneficial effects on several CD4(+) T cell mediated autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. We investigated the association of two common single nucleotide polymorphisms in the PPARA (Leu162Val) and the PPARG (Pro12Ala) genes in 116 patients with clinically definite multiple sclerosis (MS) and 211 age-matched healthy controls. The Ala allele of the PPARG Pro12Ala polymorphism was strongly associated with delayed disease onset (44.1+/-5.3 years vs 34.5+/-4.2 years; p=0.006). No significant differences were found in genotype distributions and allele frequencies of the PPARA Leu162Val and the PPARG Pro12Ala polymorphisms between MS patients and healthy controls, respectively. Our population-based study demonstrates that the Pro12Ala polymorphism resulting in an amino acid exchange in the N-terminal sequence of PPARgamma may influence the onset of MS.