Objective To explore the effect of nicotine on the degeneration of dopaminergic neurons in PD rats. Methods Forty-five SD rats were randomly divided into three groups: PBS group (CON), normal saline + LPS ( NS ) group and nicotine +LPS ( NIC ) group. On 24 hours after LPS or PBS injection, inducible nitric oxide synthase ( iNOS ) protein expression was examined by immunoblotting. ON 14d after LPS or PBS injection, the numbers of tyrosine hydroxylase ( TH ) positive neurons and morphological changes of OX-42 positive cells in the substantia nigra(SN) were observed by immunohistochemistry. TH mRNA and TH protein expressions were examined by RT-PCR or immunoblotting. Results Compared with CON group, iNOS protein increased markedly 24 hours after LPS injection in NS group. TH positive neurons, TH mRNA and TH protein in the SN decreased remarkably 14 days after nigrainjiection. Most of microlglial showed big cell body with thicker and shorter processes. However, nicotine reversed the above changes, Compared with NS group, TH positive neurons, TH mRNA and TH protein in the SN increased remarkably in NIC. Besides, most microglia showed small cell body with slim and long processes. Conclusion Nicotine could prevent LPSinduced degeneration of DA neurons, probably because of that the pretreatment with nicotine blocks the activation of microglia and the expression iNOS protein.