Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting 1 to 3% of individuals over the age of 65 years. Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between coffee consumption and PD. This study was designed to investigate the beneficial effect of caffeine in an early model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated with caffeine (20 mg/kg) 1 hour before and treated twice a day for one month. Apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were measured. Statistical analysis of the total net number of rotations made over a 60-min period 4 weeks after the surgery showed that apomorphine caused a very significant contralateral turning in the rats of the lesion (L) group (P<0.001) and induced less significant rotations in the caffeine-treated lesion (L+C) group (P<0.005) in comparison with the SH group. The results of histological studies demonstrated that although there was no significant difference for the number of Nissl-stained neurons on the right and left sides of SNC in SH group, but a significant reduction was observed for L (P<0.001) and L+C (P<0.05) groups. Meanwhile, there was no significant difference between SH and L+C groups when comparing number of Nissl-stained neurons on the left side of SNC. It can be concluded that caffeine administration attenuates rotational behavior and protect the neurons of SNC against 6-OHDA toxicity.