This study was performed to demonstrate accumulation of the photosensitizer hematoporphyrin derivative (HPD) in atherosclerosis and to determine whether intimal hyperplasia, the main cause of restenosis after angioplasty, can be inhibited by photodynamic therapy (PDT). Forty Japanese White rabbits were subjected to balloon endothelial injury in the common iliac artery. Five groups of rabbits, ie, immediately after, or 3, 7, 14 or 28 days after the balloon injury, were injected with HPD. These rabbits were sacrificed 24 h after HPD administration, and HPD fluorescence was investigated in the injured arteries by fluorescence microscopy. Other groups of rabbits were injected with HPD 24 h before PDT, and they were then subjected to intravascular Hg-Xe flash-lamp irradiation immediately after (0D-PDT), or 3 days (3D-PDT), 7 days (7D-PDT), or 14 days (14D-PDT) after the balloon injury. All rabbits were sacrificed 28 days after the balloon injury, and histological sections of PDT-treated arteries were examined by light microscopy. Slight, uniform HPD accumulation was observed in the injured media immediately after the balloon injury, and throughout the entire media and the neointima on day 7. On day 14, HPD accumulation had diminished in the media and increased in the intima, and on day 28 no HPD remained in the media. In the 0D- or 3D-PDT groups, no inhibition of intimal hyperplasia was observed. In contrast, there was significant inhibition of intimal hyperplasia in the 7D- and 14D-PDT groups, and the most effective inhibition was in the 7D-PDT group. This study demonstrated that PDT with HPD inhibits smooth muscle cell growth and decreases the intimal hyperplasia response in rabbits. (Jpn Circ J 1999; 63: 387 - 393)