Activation of vascular smooth muscle cells (VSMCs) represents a key event of atherosclerosis. It is triggered e.g. by the action of platelet-derived growth factor (PDGF). The polyphenol (+)-episesamin (ES) is known to block the TNF-α-induced mitogenic VSMC response. Aiming to develop novel therapeutic options e.g. by dietary supplements, we studied if ES and its stereoisomer sesamin (SE) reduce PDGF-BB-induced growth and migration, which both promote atherosclerosis. ES and SE reduced basal and PDGF-BB-induced proliferation and migration of human, murine and rat VSMC by impaired activation of MAPK and PI3K pathways and reduced oxidative stress by induction of haem oxygenase-1 expression. Moreover, ES and SE blocked PDGF-BB-induced activation of NF-κB with subsequently reduced expression and secretion of the gelatinases matrix-metalloproteinase-(MMP)-2 and MMP-9. In conjunction with their natural origin and well-tolerable properties, these data suggest ES and SE as potential candidates for a complemental treatment of VSMC specific vascular diseases like atherosclerosis.