Objective: To clinically evaluate a new photosensitizer, m- tetra(hydroxyphenyl) chlorin (m-THPC), for the photodynamic therapy of early squamous cell carcinomas of the upper aerodigestive tract. Design: Phase 1 included evaluation of the innocuousness of the compound after intravenous injection (control of vital parameters and blood analysis before and after injection) and evaluation of the duration of skin photosensitization. Phase 2 included assessment of optimal conditions for treatment (injected dose, drug- light interval, light dose, wavelength, etc), on 33 early squamous cell carcinomas of the mouth, esophagus, and bronchi, with a mean follow-up of 14 months; irradiation tests on healthy and neoplastic mucosae to determine the irradiation conditions that lead to tumor eradication with minimal damage to the surrounding normal mucosa and muscle layers; and localization of the dye in various tissue compartments and cells at different time intervals after the injection of the photosensitizer, by using a fluorescence microscope to analyze 46 biopsy specimens taken during the treatment sessions and 8 resected specimens of early cancers, excised with the carbon dioxide laser. Setting: Endoscopic medical center of an otolaryngology-head and neck surgery department. Patients: Twenty-five patients treated previously for a head and neck cancer with a synchronous or metachronous early second primary cancer. Patients with porphyria were excluded from the trial. Results: The best results in the bronchi and mouth were obtained with an injected dose of 0.15 mg of m-THPC per kilogram of body weight 4 days before irradiation. The fluence was 7 to 16J/cm 2, and the fluence rate was between 100 and 150 mW/cm 2 using red light at 652 nm. In the esophagus, green light at 514 nm is preferred to the red light to avoid fistulas. Optimal irradiation conditions at this wavelength, which was also used in the trachea, were found at a fluence of 75 to 100J/cm 2 and a fluence rate between 70 and 100 mW/cm 2. Of 33 lesions treated thus far by photodynamic therapy with m-THPC, 28 show no recurrence with a mean follow-up of 14 months. Photosensitivity to sunlight does not exceed 6 weeks. Conclusions: m-Tetra(hydroxyphenyl) chlorin is a second-generation photosensitizer that has several significant advantages as compared with the first-generation porphyrin mixtures hematoporphyrin derivative and porfimer sodium (Photofrin II). It is a pure compound that is 100 times more phototoxic at 652 nm and 10 times more phototoxic at 514 nm, has better selectivity for early carcinomas, and a shorter duration of skin photosensitivity. The therapeutic results indicate a recurrence rate thai is similar to that obtained with Photofrin II, ie, about 15%.