Iron-mediated oxidative stress occurs in a wide variety of neurological disorders. The present study has investigated whether melatonin can alter the proportion of neurons that die in the 24 h period following 1.0 microl intracortical injections of 1.0 mM ferric ammonium citrate (FAC) or 0.9% saline. Rats which received systemic infusions of melatonin (5 mg/kg body weight per day) displayed a 40% reduction (P = 0.019) in the proportion of neurons killed by FAC. By contrast, reduction of endogenous melatonin by continuous light exposure did not significantly affect the extent of neuronal death. Furthermore, elevated or reduced melatonin levels did not alter the number of neurons killed by saline injections. We conclude that pharmacological concentrations of melatonin protect neurons against iron-induced injury.