Arterial wall perforation and chronic restenosis represent important factors limiting the clinical application of laser angioplasty. Discrimination of normal and atherosclerotic vessels by laser-excited fluorescence spectroscopy may offer a means of targeting plaque ablation, thereby reducing the frequency of restenosis and transmural perforation. In this study, with use of a 325 nm low power helium-cadmium laser, in vivo endogenous surface fluorescence was excited through a flexible 200 microns optical fiber within a 0.018 in. (0.046 cm) guide wire in contact with the intima of 268 vascular interrogation sites from 48 patients either during open heart surgery or during percutaneous catheterization procedures. Fluorescence spectra could be recorded in all patients in bloodless and blood-filled arteries. Endogenous surface fluorescence was analyzed measuring peak intensity, peak position and shape index of the spectra. Compared with normal wall, noncalcified and calcified coronary atheroma showed a 42% (p less than 0.001) and a 58% (p less than 0.001) decrease of peak intensity, and higher shape index (p less than 0.001 and p less than 0.01, respectively). In addition, peak position was shifted to longer wavelengths for noncalcified coronary atheroma (p less than 0.001). Compared with normal aorta sites, aortic plaques demonstrated a 46% decrease of peak intensity, longer peak position wavelengths (p less than 0.05) and a higher shape index (p less than 0.001). Using an atheroma detection algorithm, prospective analysis of aorta and coronary spectra showed a specificity of 100% for identifying normal sites and a sensitivity of 73% for recognizing atherosclerotic sites.(ABSTRACT TRUNCATED AT 250 WORDS)