Cutaneous drug reactions (CDR) are responsible for numerous minor to life-threatening complications. Though the exact mechanism for CDR is not completely understood, evidence suggests that bioactivation of drugs to reactive oxygen or nitrogen species is an important factor in the initiation of these reactions. Several CDR-inducing drugs having an arylamine functional group, such as sulfamethoxazole (SMX) and dapsone (DDS), undergo bioactivation to reactive arylhydroxylamine metabolites. These metabolites can generate cellular oxidative stress by forming reactive oxygen species (ROS). Several studies have demonstrated a higher cytotoxicity with DDS hydroxylamine (DDS-NOH) compared to SMX hydroxylamine (SMX-NOH). To investigate the role of differential ROS generation in the higher cytotoxicity of DDS-NOH, hydroxylamine metabolites of SMX and DDS were synthesized and ROS formation by these metabolites determined. DDS-NOH and its analogues/metabolites consistently resulted in higher ROS formation as compared to SMX-NOH. However, comparison of the ROS generation and cytotoxicity of a series of arylhydroxylamine analogues of DDS did not support a simple correlation between ROS generation and cell death. Numerous ROS scavengers were found to reduce metabolite-induced ROS formation, with differences in the potency between the agents. The decrease in DDS-NOH-induced ROS generation in NHEK with ascorbic acid, N-acetylcysteine, Trolox, and melatonin was 87, 86, 44, and 16%, respectively. Similarly, the cytotoxicity and adduct formation of DDS-NOH in NHEK was reduced in the presence of ascorbic acid. In summary, these studies show that arylhydroxylamine metabolites of SMX/DDS induce ROS generation in NHEK, though such generation is not directly related to cytotoxicity.