OBJECTIVE To investigate the effectiveness of photodynamic therapy (PDT) in eliminating proliferating vascular smooth muscle cells (VSMCs). This may have a potential role in reducing restenosis rates clinically. METHODS Human VSMCs were successfully cultured from 15 long saphenous veins (SV) and seven restenotic lesions (RL) removed during revision coronary and peripheral vein graft surgery. Cultured VSMCs were incubated with photofrin at doses of 0-5 micrograms/ml for 48 h, and then exposed to 4 J/cm2 of polychromatic light. Cell destruction was quantified by a colorimetric assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. RESULTS Results are expressed as a mean percentage survival +/- standard error. Cells were minimally affected by either photofrin alone (SV: 95.5% +/- 5.3; RL: 119.8 +/- 4.8) or light alone (SV: 75.38% +/- 3.99; RL: 100.1 +/- 11.0). The combination of 2 micrograms/ml of photofrin and 4 J/cm2 of polychromatic light energy, i.e. PDT, was severely toxic to cells derived from saphenous veins (5.52% +/- 0.85) as well as cells derived from restenotic lesions (9.6 +/- 2.3). These doses are comparable to doses that can be achieved in vivo. CONCLUSIONS PDT in the appropriate drug and light doses can eliminate human VSMCs, including those responsible for vascular restenosis.