The nervous system is the primary target for low-levels of lead (Pb) exposure and the developing brain appears to be especially vulnerable to Pb neurotoxicity. Chronic low-level Pb exposure causes growth retardation and intellectual impairment. In the present study the protective effect of melatonin during exposure to low-levels of Pb in human SH-SY5Y neuroblastoma cell cultures was assessed. The cells were exposed to Pb (0.01 to 10 microM) for 48 h. Pb inhibited the proliferation of neuroblastoma cells significantly in a concentration-dependent manner. A 50% inhibition (IC50) of cell proliferation was observed at about 5 microM Pb. Pb decreased (16% to 62%) the levels of total cellular glutathione (GSH) in a concentration (0.1 to 10 microM)-dependent manner. Exposure of cells to Pb (5 microM) for 48 h resulted in an eightfold increase in caspase-3 activity and prostaglandin E2 (PGE2) level. Pretreatment with melatonin (10 microM) blocked the effects of Pb on GSH content and caspase-3 activity, and showed significant improvement in reducing the level of PGE2. The results suggest that some of the neurotoxic effects of Pb may be partly mediated by apoptosis and pretreatment with melatonin can prevent these effects. The present study asserts the neuroprotective effect of melatonin in conditions of Pb-induced toxicity in neuroblastoma cell cultures.