The long-term benefit of coronary or peripheral vascular interventions is limited by restenosis, due to intimal hyperplasia (IH). Photodynamic therapy (PDT) with systematic delivery of the photosensitizing drug, performed either at the time or shortly after vascular injury, has been demonstrated to effectively inhibit the development of experimental IH. However, in order to deliver large quantities of the photosensitizer, but avoid systematic photosensitization, local delivery of the drug appears to be an advantageous option. An experimental model was therefore developed to deliver benzporphyrin derivative (BPD-MA) directly into isolated segments of balloon-injured rat common carotid arteries, and to study the uptake in serum and arterial tissue by means of spectrofluorometry. Furthermore, early effects of local versus systematic drug delivery and subsequent PDT treatment, were investigated with light microscopy and morphometric analysis. Local delivery of BPD lead to effective drug concentrations in the artery with complete depletion of endothelial and smooth muscle cells, already 24 h after PDT. The media appeared compacted and acellular. No thrombosis or occlusion were observed. Serum concentrations of BPD, after local delivery, were at the detection threshold, whereas systematic application resulted in significantly higher serum but equivalent tissue drug concentrations. In conclusion, these data demonstrate that local delivery of BPD results in tissue concentrations, appropriate to perform an efficient vascular PDT treatment of the arterial wall.