Cimetidine is one of the most potent H(2) receptor antagonists for inhibiting excessive histamine-induced acid secretion and is currently used worldwide to treat peptic ulcers. In this study, levels of free radicals were assessed and the ability of cimetidine to act as an antioxidant was determined using nitroblue-tetrazolium assay and lipid peroxidation assays. Free radical generation in the brain is promoted by the presence of iron, as occurs in the Fenton reaction. The results show that cimetidine reduces the generation of superoxide anion formed in the nitroblue-tetrazolium assay. In addition, cimetidine (1 mM) is able to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates. Electrochemistry, UV/Vis spectroscopy and HPLC experiments show metal-ligand interactions between cimetidine and transition metals. The results imply that cimetidine provides a neuroprotective effect by binding to iron and copper, thus making them unavailable for free radical production.