The disruption of endothelial homeostasis is the hallmark of coronary artery disease (CAD) and psychological disorders such as anxiety/depression. Xinkeshu (XKS), a traditional Chinese patent medicine, plays an essential role in CAD and psychological condition; however, the mechanisms underlying the effects of XKS on the endothelial function and endogenous endothelium-repair capacity in CAD patients with anxiety/depression remain elusive. In this study, endothelial function and endothelial progenitor cell- (EPC-) mediated reendothelialization capacity were compared among age-matched healthy subjects, CAD patients with or without anxiety/depression. Besides, CAD patients with anxiety/depression received 1-month XKS treatment. Anxiety/depression symptoms were evaluated by Generalized Anxiety Disorder 7-item (GAD-7)/Patient Health Questionnaire-9 (PHQ-9) score, endothelial function was tested by flow mediated dilation (FMD) measurement, and EPC-mediated reendothelialization capacity was evaluated by a carotid artery injury model in nude mouse (n=6) with the injection of XKS-incubated EPCs from CAD patients with anxiety/depression. The results showed that FMD and EPC-mediated reendothelialization capacity of CAD patients with anxiety/depression were compromised compared to healthy subjects and CAD patients without anxiety/depression. After 1 month of XKS treatment, FMD increased from 4.29 +/- 1.65 to 4.87 +/- 1.58% (P<0.05) in CAD patients with anxiety/depression, whereas it remained unchanged in the controls. Moreover, XKS decreased GAD-7 and PHQ-9 scores. Meanwhile, incubating XKS enhanced in vivo reendothelialization capacity and in vitro apoptosis of EPCs from CAD patients with anxiety/depression, which was associated with the upregulation of CXC-chemokine receptor 7 (CXCR7) and inhibition of phosphorylation of p38 signaling. CXCR7 knockdown abolished the beneficial effects of XKS, which was rescued by p38 inhibitor SB203580. Our data demonstrate for the first time that XKS improves endothelial function and enhances EPC-mediated reendothelialization through CXCR7/p38/cleaved casepase-3 signaling and provides novel insight into the detailed mechanism of XKS in maintaining endothelial homeostasis in CAD patients with anxiety/depression.