A large proportion of patients with coronary artery disease (CAD) suffer from depression or anxiety symptoms and this is associated with increased mortality [1]. This double-blinded, randomized, placebo-controlled, clinical trial (ChiCTR-IPR-17010940) aimed to explore whether Xinkeshu tablets can reduce anxiety or depressive symptoms in CAD patients and how this is related to the concentration of plasma cytokines. Sixty patients with CAD and a Hospital Anxiety and Depression Scale (HADS-a/HADS-d) score of >= 8 were treated with Xinkeshu tablets or placebo for 12 weeks following percutaneous revascularization. Depressive/anxiety symptoms and the levels of 440 peripheral blood cytokines were evaluated at baseline and after 12 weeks treatment. Results showed significantly lower (P < 0.05) HADS-a/HADS-d and PHQ-9 scores in CAD patients treated with Xinkeshu tablets than in those who received placebo. These improvements were associated with changes in certain peripheral blood cytokines; most notably trappin-2, adiponectin, interleukin 1 beta (IL-1 beta), thrombopoietin, activated leukocyte cell adhesion molecule (ALCAM), neurotrophin-3 (NT-3), and transferrin. A significant correlation between anxiety/depression symptoms and trappin-2, NT-3, transferrin, and ALCAM (p < 0.05) were observed in an independent cohort of patients with CAD. These findings were in-keeping with the antidepressive effects of Xinkeshu tablets. This trial demonstrates that Xinkeshu tablets can improve anxiety and depression symtoms effectively address in patients with coronary heart disease possibly through increasing the blood ratio of anti-inflammatory: pro-inflammatory cytokines.