Objective: To observe the effect of puerarin on methyl-CpG binding protein 2 (MeCP2) phosphorylation (pMeCP2) in the hippocampus of a rat model of vascular dementia (VD). Methods: Thirty-six healthy Sprague-Dawley rats were randomly assigned to the sham-operated group, dementia group and puerarintreated group using a random number table (n=12 per group). The modified permanent bilateral common carotid artery occlusion method was used to establish the VD model. The sham-operated and dementia groups were given 2 mL/d of saline, while the puerarin-treated group was given 100 mg/(kg·d) of puerarin for 17 days. The learning and memory abilities were evaluated by the Morris water maze test. Hematoxylin-eosin staining, immunohistochemical (IHC) staining and Western blot analysis were carried out to observe changes in neuron morphology and in level of pMeCP2 in the hippocampus, respectively. Results: The morphologies of rat hippocampal neurons in the puerarintreated group were markedly improved compared with the dementia group. The escape latency of the dementia group was significantly longer than the sham-operated group (P＜0.05), while the puerarin-treated group was obviously shorter than the dementia group (P＜0.05). Cross-platform times of the dementia group were significantly decreased compared with the sham-operated group (P＜0.05), while the puerarin-treated group was obviously increased compared with the dementia group (P＜0.05). IHC staining showed no significant difference in the number of MeCP2 positive cells among 3 groups (P＞0.05). The number of pMeCP2 positive cells in the CA1 region of hippocampus in the dementia group was significantly increased compared with the sham-operated group, and the puerarin-treated group was significantly increased compared with the dementia group (both P＜0.05). Western blot analysis showed no significant difference of MeCP2 expression among 3 groups (P＞0.05). The expression of pMeCP2 in the dementia group was significantly increased compared with the sham-operated group, while it in the puerarin-treated group was significantly increased compared with the dementia group (P＜0.05). Conclusion: Puerarin could play a role in the protection of nerve cells through up-regulating pMeCP2 in the hippocampus, improving neuron morphologies, and enhancing learning and memory ablities in a rat model of VD.