AIM To investigate the neuroprotective effects of lesion and high frequency stimulation(HFS) of the subthalamic nucleus (SIN) on the substantia nigra pars compacta(SNc) neurons and its probable mechanism. METHODS The PD models were induced by unilateral administration of 6-hydroxydopamine into right substantia nigra in rats. After the high-frequence stimulation to SIN and injection of ibotenic acid to STN on PD rats, the changes of behavior were observed. The substantia nigra neurons were detected by using special-dyeing, TUNEL techniques and immunohistochemistry methods. RESULTS In the stimulation group, the apoptotic rate was significantly lower than PD model group and lesion group (P < 0.05). Compared with normal rats, model group and lesion one had the similar results of expression of Bcl-2, Bax and their ratio, which were lower expression of Bcl-2, higher expression of Bax and the decrease of their ratio (P < 0.05). In the stimulation group, the expression of Bcl-2 and Bcl-2/Bax were much higher than model group and lesion group. The number of apoptotic neurons of rats in lesion group was smaller than model ones (P < 0.05), but there was no significant difference in expression of Bcl-2, Bax and their ratio (P > 0.05). CONCLUSION Lesion or HFS of STN have the neuroprotective effects on SNc neurons of PD rats, and HFS has a better long-term effect.