Photosensitization of atherosclerotic (Ath) plaque with exogenous chromophores may confine laser irradiation (LI) injury to Ath plaque and allow safer and more efficacious laser angioplasty. Dihematoporphyrin ether (DHE) accumulates preferentially in plaque, and previous in vitro LI studies have shown confinement of LI injury to plaque. To further evaluate DHE enhanced laser angioplasty, 5 Ath Yucatan miniswine with 8 iliofemoral stenoses (Sten) were treated with 2.5 mg/kg of DHE IV. Twenty-four hours later, 632 nm continuous wave LI was delivered to Sten using 200mu core optical fiber with a 582mu x 1cm diffusing tip. Angiograms were performed before, immediately after, and two weeks following LI. 6 of 8 vessels showed improvement. Control mean Sten was 71%, immediate post LI was 55% and 2 weeks post LI was 19% Sten. In 4 of 6 responding vessels, there was 0% Sten at 2 weeks post LI and the previously stenotic segments appeared normal. 2 of 6 responders showed only modest improvement, from control mean Sten of 83% to 55% Sten at 2 weeks. 2 of 8 vessels showed no improvement. There were no perforations or dissections. The excellent results in some vessels demonstrate the potential of photosensitizer enhanced LI as very effective primary therapy of Ath. The time course of improvement indicates that both immediate thermal and delayed photochemical (photodynamic therapy) effects are operative. Further studies are required to identify reasons for failure in some vessels.