Treatment of advanced carcinomas of the head and neck may benefit from adjuvant photodynamic therapy and brachyradiotherapy. To date, however, there has been no controlled study to evaluate whether high-dose irradiation can be safely accomplished without major tissue reaction in the presence of high circulating doses of Photofrin, the photosensitizing agent used in photodynamic therapy. Thirty adult male white rats were involved in the study. Fifteen rats received Photofrin 5 mg/kg intravenously, and 15 rats received the same volume of sterile saline intravenously. At 48 hours following injection, each rat received 1,000 cGy of radiation to a 3 x 5 cm area of dorsal skin using a cobalt linear accelerator unit. Skin changes postradiation were observed for degree of erythema, blistering, necrosis, and sloughing. Five rats from the Photofrin and control radiation groups were sacrificed on days 2, 7, and 21 postradiotherapy. Skin changes in each animal were identical with mild erythema lasting from 10-14 days postradiotherapy. There was no evidence of blistering, necrosis, or sloughing of skin in any of the animals studied. Histologic evaluation of the irradiated skin after sacrifice demonstrated no difference between the Photofrin and saline-irradiated groups. As well, the histologic recovery from acute radiation injury was also identical. This controlled study demonstrates that radiation therapy may be safely administered without increased morbidity when tissue concentrations necessary to perform photodynamic therapy are present.