Abstract: The finding that the amyloid β protein (Aβ) has neurotoxic properties and that such effects are partly mediated by free radicals has provided insights into the mechanisms of cell death in Alzheimer's disease (AD) and an avenue to explore new therapeutic approaches. Melatonin is a potent antioxidant and free radical scavenger. Previously, we showed that long-term application of melatonin alleviated the learning and memory deficits in the APP695 transgenic mouse model of AD. In this study, the importance of melatonin in the management of Aβ-induced apoptosis was investigated. Rat pheochromocytoma (PC12) cells treated with either Aβ25–35 or Aβ1–42 underwent apoptosis. Melatonin pretreatment at 10−5, 10−6 and 10−7 m significantly attenuated Aβ25–35- or Aβ1–42-induced apoptosis in PC12 cells. The anti-apoptotic effects of melatonin were highly reproducible and corroborated by multiple quantitative methods, including MTT cell viability assay, Hoechst 33342 nuclei staining, DNA fragmentation analysis, and flow cytometric analysis. In addition, melatonin effectively suppressed Aβ1–42-induced nitric oxide formation, potently prevented Aβ1–40-induced intracellular calcium overload and significantly alleviated Aβ1–40-induced membrane rigidity. These results suggest that the mechanism of Aβ neurotoxicity involves oxidative stress, and the neuroprotective effects of melatonin are, at least in part, associated with its antioxidant properties. The use of melatonin or its derived analogs should be explored as a therapeutic approach in AD.