Background: Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge. Objective: To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers. Design: Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics. Patients: Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease). Methods: A single intravenous infusion of 14 mg/m2 of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm2 of red light (688 ± 10 nm) from a light-emitting diode panel. Main Outcome Measures: Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months. Results: The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm2 to 93% at 180 J/cm 2. At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm2 to 95% at 180 J/cm2. No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months. Conclusion: A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.