The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes (alpha, beta/delta, and gamma). PPAR delta is ubiquitously expressed and involved in lipid and glucose metabolism. However, the effect of PPAR delta on vascular smooth muscle cell (VSMC) proliferation and migration has not been fully elucidated yet. Here, we investigated the effect of L-165041, a selective ligand for PPAR delta, on PDGF-induced rat VSMC proliferation. Our data show that L-165041 inhibited rat VSMC proliferation in a dose dependent manner by blocking G(1) to S phase progression and repressing the phosphorylation of retinoblastoma protein (Rb). Furthermore, L-165041 inhibited PDGF-induced expression of cyclin D1 and CDK4. These effects less likely involve PPAR gamma pathway because PPAR gamma antagonist GW9662 pretreatment failed to reverse the inhibitory effect of L-165041 on rVSMC proliferation and migration. For in vivo studies, L-165041 was administered to Sprague-Dawley rats using osmotic pumps before and after the carotid balloon injury, and L-165041 decreased neointima formation after the carotid injury. In conclusion, our results suggest that PPAR delta ligand L-165041 can be a therapeutic agent to control pathologic cardiovascular conditions such as restenosis and atherosclerosis.