Light is known to interact with endogenous or exogenous chemical agents in the skin or eyes, to produce photosensitization (phototoxicity or photoallergy). While the initial step in all forms of photosensitivity must be the absorption of light by the chemical or its metabolites, the precise mechanisms of sensitization are unknwon. The objective of this study is to determine whether light-induced free radicals or active oxygen species play a role in photosensitization. Benoxaprofen [2-(4-chlorophenyl)-Alpha-methyl-5-benzoxazole acetic acid] is an anti-inflammatory drug that causes acute phototoxicity in many patients. Irradiation of benoxaprofen in anerobic organic solvents provided evidence for hydrogen abstraction reactions and a drug-derived carbon centered radical. In the presence of oxygen both superoxide and singlet oxygen were detected. Oxygen markedly increased the photohemolysis of human red blood cells by benoxaprofen suggesting that oxygen-derived species were involved. Inhibition of photohemolysis by the anti-oxidant butylated hydroxyanisole emphasized the importance of free radicals in this process. Anthracene, a component of coal tar, is a potent photosensitizing agent both in vivo and in vitro. Irradiation of anthracene in aerated ethanol produced singlet oxygen. Anthracene caused a concentration dependent photohemolysis of human erythrocytes that was markedly enhanced by the presence of oxygen and was abolished by Beta-carotene, a singlet oxygen quencher. These findings are consistent with the generation of singlet oxygen by irradiated anthracene, which in turn reacts with membrane lipids to produce peroxides that are responsible for membrane damage and, ultimately, hemolysis. Irradiation of the following chemical agents in aqueous or organic solvents also produced free radicals and/or active oxygen species: benzoxazole, 2-methylbenzoxazole, 2-phenylbenzoxazole, musk ambrette, chlorpromazine, furosemide and fluoranthene. These photoinduced species may play an important role in the phototoxic and photoallergic properties of these agents.