Objective To study the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) tail vein transplantation on depressive behavior in chronic unpredictable mild stress (CUMS) model mice. Methods The third generation hUCMSCs were abtained; Sixty C57BL/6 male mice were randomly divided into the normal model group (+ normal saline), the cell group (+hUCMSCs) and the fluoxetine(flu) group (+flu), with 15 mice in each group. The depression model of CUMS mice with a 6 week duration was constructed; From the third week, hUCMSCs and normal saline were transplanted into the mice by tail vein injection, and the mice were gavaged with flu daily from the fifth week; Weight changes in each group were recorded weekly; The depression model and therapeutic effect of mice were evaluated by sucrose preference test, tail suspension test, forced swimming test and open field test; The cell changes of CAI and CA3 region in hippocampus were observed by HE staining; Transmission electron microscopy was used to detect the changes of synapses in CA3 region of hippocampus; Real-time PCR was used to detect mRNA expressions of synaphysin (SYP) and postsynaptic density protein 95 (PSD-95), which are key proteins of synaptic plasticity. Results hUCMSCs improved weight decrease in depressed mice; behavioral experiments observed that the model group mice showed depressive behavior, while the cell group and the drug group mice depression were improved; HE staining showed that, compared with the model group, cells in CA 1 and CA3 regions of the hippocampus of mice in the cell group and the group were arranged orderly and the number of cells increased; Transmission electron microscopy showed that compared with the model group, the number of synapses in the CA3 region of the hippocampus was more, the synaptic gap was narrower, and the density of synaptic spines was higher in the cell group and the drug group; More mRNA expressions of SYP and PSD-95 were detected by Real-time PCR in the cell group and the drug group than in the model group. Conclusion hUCMSCs transplatation showes antidepressant effects, which are associated with improved synaptic plasticity in the hippocampus.