Abstract： Objective To explore the mechanism through which nicotine protects dopaminergic neurons against 6-hydroxydopamine (6-OHDA) toxicity in Parkinson's disease (PD) rat model. Methods Sixty Female SD rats were divided into 3 groups according to randomly digital table: High dosage group (nicotine 2 mg/kg, 5 injections I.p. Per day at 2-h interval), low dosage group (nicotine 0.2 mg/kg, 5 injections I.p. Per day at 2-h interval) and model group (normal saline treatment), n=20 each group. On day 8 after the treatment, a single injection of 20 ug of 6-OHDA was administered into striatum. Nicotine or normal saline was administered continuously daily until animals were killed. The dopaminergic neurons and CD3, CD4 and CDS-positive lymphocytes were analyzed quantitatively using immunohistochemistry and stereology. Results Four weeks after 6-OHDA administration, in the normal saline treated group, tyrosine hydroxylase-immunopositive cells in the substantia nigra of administered side was 25.27% of those in the one of non-administered side, and the immunopositive cells in 0.2 and 2 mg/kg nicotine treated groups were respectively 64.97% and 67.24% of those in the non-administered side. The loss of dopaminergic neurons induced by 6-OHDA in the substantia nigra was significantly less severe in the nicotine treatment groups (at both 0.2 and 2 mg/kg groups) than the saline treated group. T lymphocyte infiltration was markedly induced by 6-OHDA administration into striatum in all groups. In the striatum, we observed that the numbers of CD3, CD4 and CD8-positive lymphocytes were reduced significantly in the nicotine treated animals as compared to saline controls (P<0.05). The proportions of CD4 and CD8 positive cells in the total T lymphocytes were roughly equivalent in all groups at all time points, and there were no significant difference between nicotine treated groups and saline treated group. Conclusion Nicotine may have a neuroprotective effect against 6-OHDA induced dopaminergic lesion by inhibiting the infiltration of T lymphocytes and inflammation.