Photodynamic therapy (PDT) is emerging as an effective therapy for a variety of malignant diseases, including head and neck cancer. Prolonged cutaneous photosensitivity following therapy, however, remains the most significant side effect. The biochemical mechanism of this sensitivity, and indeed of the tumoricidal effect of PDT, is uncertain, but is believed to involve formation of singlet oxygen and possibly other oxygen-derived free radicals. This laboratory recently reported that a singlet oxygen scavenger, diphenylisobenzofuran (DPIBF), afforded cutaneous photoprotection to 67% of animals treated with PDT. Those results, the first from an in vivo study, supported the idea that singlet oxygen plays a significant role in PDT and its associated toxicity. They also, however, suggested that it is not the sole intermediate. The current study looks at the photoprotective effects of the hydroxyl radical scavenger dimethyl thiourea, alone and in conjunction with DPIBF. Our results strongly support a role for the hydroxyl radical in producing the cutaneous phototoxicity associated with PDT. © 1991.