In this study, the protective effects of melatonin were evaluated against 3-nitropropionic acid (3-NP)-induced striatal neuronal damage in rats. Lesions were induced in the right striatum of Sprague-Dawley rats by stereotaxic injection with 3-NP and melatonin was intraperitoneally administered both 30 min before and 60 min after 3-NP injection. And rats continuously received melatonin daily for 3 days. As indicators of oxidative damage, lipid peroxidation and protein oxidation in the lesioned striatum were measured at 1 day after 3-NP injection. Levels of malondialdehyde (MDA) and protein carbonyl were significantly increased by 3-NP injection, but reduced in the melatonin-treated rats. Four days post-lesion, large lesions and extensive neuronal damage were produced in the 3-NP-injected striata, as revealed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. In addition, marked ipsilateral rotational behavior following apomorphine challenge and a decrease of dopamine content in the lesioned striatum were observed in the 3-NP-injected rats. However, melatonin treatment significantly attenuated the 3-NP-induced neuronal damage, reduced the degree of asymmetric rotational behavior, and restored the dopamine level in the lesioned striatum. The present results indicate that melatonin effectively protects against the neuronal damage caused by 3-NP in vivo and that the neuroprotective effects of melatonin may be related to antioxidant action.