Background: Rasagiline is a selective monoamine oxidase (MAO) B inhibitor which has been approved for treatment of Parkinson's disease (PD). Objectives: This study was performed to evaluate rotenone neurotoxicity in mice and to investigate the possible neuroprotective effect of rasagiline and its mechanism. Methods: Thirty six male mice were used and divided into three equal groups. The first group, the control group, received only sunflower oil intraperitoneally (IP) once daily at a volume of 4 ml/kg for 49 days. The second group was given rotenone (2 mg/kg/day; IP) for 49 days. The third group was given rasagiline (1 mg/kg, IP) which was administered 30 min prior to rotenone (2 mg/kg/day; IP) for 49 days. Behavioral tests were performed a day prior to drug administration and then once weekly along the duration of drugs or vehicle administration. At the end of the 49 days all animals were sacrificed and their midbrains were subjected to immunohistochemical analysis for dopaminergic neurons staining for anti-tyrosine hydroxylase (TH) antibodies. Midbrain tissues were also isolated for biochemical measurements. Results: Rasagiline administration significantly improved the mice activity. Pretreatment with rasagiline significantly attenuated rotenone-induced midbrain dopamine loss. Moreover, rasagiline treatment also significantly prevented the loss of TH immunoreactive neurons within the substantia nigra pars compacta (SNpc). Furthermore, rasagiline inhibited the remarkable decrease in total antioxidant capacity as well as the increase in the malondialdehyde (MDA) level and nitric oxide generation induced by chronic rotenone administration. Conclusion: These results suggest that chronic intraperitoneal administration of rotenone induced PD-like disorder in mice. Moreover, these results suggest that rasagiline had neuroprotective effect against the rotenone-induced PD. This neuroprotective effect was mediated even in part by the antioxidant properties of rasagiline.