A significant component of restenosis after coronary angioplasty is due to medial proliferation. Targeted ablation of the proliferating cells by ionizing radiation may prevent restenosis. We delivered high-dose intracoronary gamma-irradiation in porcine coronary arteries and assessed vasomotor function acutely and at 32 days, with pathological analysis at 32 days. Changes in luminal area were assessed by intravascular ultrasound. Irradiated segments acutely displayed vasoconstriction to acetylcholine, with loss of smooth muscle response to nitroglycerin. Restudy revealed restoration of normal vasodilatory response to acetylcholine but persistent loss of response to nitroglycerin. Histopathology at 32 days revealed minor neointima formation without luminal compromise and diffuse fibrosis of the smooth muscle layer. The surrounding myocardium was normal. Focal medial fibrosis without significant endothelial or myocardial damage can be achieved via this technique; intracoronary irradiation, therefore, may be an effective way of impairing the restenosis process.