Smooth muscle cell proliferation plays a major role in restenosis following angioplasty. We have studied the effects of ultraviolet A (UVA) activation of 8-methoxypsoralen (8-MOP) on cultured SMC as well as atherosclerotic rabbit femoral arteries following angioplasty. 8-MOP and UVA display synergistic proliferation inhibition of cultured SMC in a cell-cycle independent manner. At intermediate doses, a cytostatic effect was seen over a 28 day period following a single exposure. In conclusion, a combination of 8-MOP and UVA significantly lowered SMC proliferation and cellularity in cell culture as well as in the neointima and media after balloon-induced vascular injury in the atherosclerotic rabbit model. This approach of systemic administration and local activation is feasible and offers a potential therapy for restenosis.