BACKGROUND Photodynamic therapy (PDT) currently is approved for the palliative treatment of malignancies of the aerodigestive tract using laser‐activated porfimer sodium. A new approach has been developed, based on intratumoral placement of a nonlaser light device that activates talaporfin sodium, that may expand the use of PDT to include a broader range of treatment‐resistant malignancies. The safety of this approach was assessed in a Phase I study in patients with locally advanced, refractory tumors. METHODS Twenty‐one patients with radiation‐resistant or chemotherapy‐resistant or inoperable malignancies were enrolled in four cohorts representing four light doses. Patients were treated with a single intratumoral light device and a fixed photosensitizer dose. Safety assessments were based on review of adverse events (AEs) and serious adverse events (SAEs), and independent evaluation of computed tomography (CT) images. RESULTS The observed occurrence of treatment‐related AEs and SAEs was minimal. No cutaneous phototoxicity was observed in any patient. The overall observed tumor response rate was 33%. CONCLUSIONS Photoactivation of talaporfin sodium using intratumoral nonlaser light was found to be safe in the patient population of the current study at all light dose levels tested. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11708 A Phase I study of talaporfin sodium that was photoactivated by a minimally invasive intratumoral light device was conducted in patients with refractory tumors. Observed adverse and serious adverse events were minimal and an overall tumor response rate of 33% was observed.