Abstract: Objective To explore the possible mechanisms of ginsenoside Rh2 in alleviating antidepressant-like effects in chronic social defeat stress(CSDS) mice.Methods A CSDS model was established using C57BL/6 J and CD1 mice. Then, based on social interaction ratio, sensitive mice were determined and divided into three groups(n=10): a CSDS group, a Rh2 treatment group, and a fluoxetine treatment group. Meanwhile, another ten C57BL/6J mice were selected as a control group. Then, the effect of Rh2 on alleviating depressive-like behaviors in CSDS mice were evaluated by sucrose preference test, forced swimming test, tail suspension test and social interation test. The levels of oxidative stress factors superoxide dismutase(SOD), glutathione peroxidase(GSH-PX), malondialdehyde(MDA) and nitric oxide(NO),as well as inflammatory factors tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interferon-γ(IFN-γ) were measured by ELISA and RT-qPCR. Furthermore, the effect of Rh2 on the changes of 4-hydroxynonenal(4-HNE), glial fibrillary acidic protein(GFAP), and doublecortin(DCX) were detected by immunofluorescence assay, real-time quantitative PCR and Western blot.Results The CSDS mouse model was successfully established. After Rh2 treatment, the depression-like behaviors in CSDS-induced mice were significantly improved, the activity of SOD and GSH-PX was enhanced, the content of MDA and NO was reduced, the level of 4-HNE was elevated, the protein and mRNA levels of IL-1β, TNF-α and IFN-γ were reduced, and neurogenesis was improved.Conclusions Rh2 can produce antidepressant-like effects on CSDS in mice, which may be associated with protection against oxidative stress and inhibition of neuronal deterioration, resulting inreduced neurogenesis.