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Objective: To explore the effect and mechanism of human adipose-derived mesenchymal stem cells (hADMSCs) on phenotypic polarization of microglia., Methods: BV-2 microglia of C57/BL6 mice were co-cultured with hADMSCs+lipopolysaccharide (LPS), or cultured with LPS alone. Cell morphology was observed under an inverted microscope. The effect of hADMSCs on microglial proliferation was evaluated by CCK-8 assay. The impact of hADMSCs on microglia M1/M2 phenotype markers were detected using quantitative real-time PCR (RT-qPCR). The affect of hADMSCs on the proteins expression levels of Toll-like receptor 4 (TLR4)-TIR domain containing adaptor protein inducing interferon β (TRIF) signaling pathway in BV-2 microglia was detected by using Western blot analysis., Results: As compared with the LPS treatment, hADMSCs treatment had no obvious effect on microglia morphology, whereas showed significant inhibition on microglial proliferation activity ( P <0.05). Simultaneously, hADMSCs treatment reduced expression of microglia M1 phenotype markers ( P <0.05), and increased microglia M1 phenotype markers in gene levels ( P <0.05). At the same time, protein expression levels of TRIF, TLR4, phosphorylated interferon regulatory factor 3 (P-IRF3) and interferon regulatory factor 3 (IRF3) in BV-2 microglia were decreased after hADMSCs treatment., Conclusion: hADMSCs can blockade the LPS-induced pro-inflammatory microglia M1 phenotype, whereas induces protective microglial M2 phenotype, which may be related to inhibition of the TLR4-TRIF signaling pathway., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)