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Previous studies have implicated both peroxidases and leukocytes in the metabolic activation of the human carcinogen diethylstilbestrol (DES). Here we demonstrate that DES is converted during the oxidative burst of human leukocytes to reactive protein binding species. Although luminol-dependent chemiluminescence indicated that peroxidase-dependent metabolism was occurring, the protein binding was not inhibitable by azide. This suggested that either peroxidase-mediated metabolism was not responsible for the formation of the reactive protein binding species or that this binding was occurring in a cellular compartment inaccessible to azide. The addition of catalase alone and in combination with superoxide dismutase (SOD) did, however, result in significant inhibition of binding. Hypochlorous acid was also shown to be capable of directly converting DES to protein binding species. These results indicate that a product of the oxidative burst, most likely a highly oxidizing species derived from H2O2, is capable of converting DES to a potentially carcinogenic binding species.