OBJECTIVE: To determine the efficacy of photodynamic therapy (PDT) with meso-tetra (hydroxyphenyl) chlorin (m-THPC) photosensitizer for recurrent respiratory papillomatosis. DESIGN: Parallel-arm, randomized trial of patients requiring surgery at least 3 times yearly with single PDT 6 or 18 months after enrollment and 12-month follow-up. Disease extent was scored and papillomas were removed during direct endoscopy every 3 months after enrollment. SETTING: Tertiary medical centers. PATIENTS: Of 23 patients aged 4 to 60 years enrolled in the study, 15 patients, plus 2 in the late group without PDT owing to airway risk, completed the study. Six patients withdrew voluntarily after PDT. INTERVENTION: Intravenous administration of m-THPC 6 days before direct endoscopic PDT with 80 to 100 J of light for adults and 60 to 80 J for children. MAIN OUTCOME MEASURES: Difference in severity scores between the early and late groups and between pre- and post-PDT scores for all patients. Secondary measures were the associations between baseline characteristics and response and changes in immune response and the prevalence of latent viral DNA. RESULTS: There were significant differences between groups, with marked improvement in laryngeal disease across time after PDT (P = .006). Five of 15 patients were in remission 12 to 15 months after treatment, but there was recurrence of disease after 3 to 5 years. Tracheal disease was not responsive to PDT. No change occurred in the prevalence of latent human papillomavirus DNA. The immune response to virus improved with clinical response. CONCLUSIONS: Use of m-THPC PDT reduces the severity of laryngeal papillomas, possibly through an improved immune response. Failure to maintain remission with time suggests that this is not an optimal treatment.