Background: Xiaoyaosan(XYS), a famous Chinese prescription, had been effectively used for the treatment of depression in clinic.Numerous of clinical studies and animal experiments indicate that XYS has obvious antidepressant activity.However, there is no report on the effect of XYS application using a metabolomics approach in patients.Aim of the study: The purpose of this study was to study the pathogenesis of depression and observe the effect of XYS on the plasma metabolism of patients with mild to moderate depression.Method: 14 patients with mild to moderate depression were enrolled as the treatment group, 16 healthy volunteers were enrolled as control group in this study.1 H nuclear magnetic resonance (NMR)-based metabonomic techniques and multivariate statistical method were used to analyze the plasma metabolites of depressed patients before and after treatment and healthy controls.Result: A clear separation of depressed patients and healthy controls was achieved, and 15 endogenous metabolites which may be related to depression were identified.By multi-group comparing, the results reveal that majority of biomarkers were reversed after 6 weeks treatment and back to normal level.The possible biochemical regulation with XYS treatment was also discussed.Conclusion: Our study shows that XYS could produce obvious antidepressant effect and NMR-based metabonomic approach shows great potential in the study of biological effect of XYS.