The aim of this study was to investigate whether C1q/TNF-related protein 9 (CTRP9) could stabilize the mature plaques by targeting macrophages in the apolipoprotein E knockout (ApoE KO) mice model. In vivo, the mice were subjected to high-fat diet and constrictive collars on the right carotid artery for eight weeks, a lentiviral vectors expressing CTRP9 (LV-CTRP9) or green fluorescence protein (LV-eGFP) as a control was intravenously injected into ApoE KO mice. Delivery of LV-CTRP9 resulted in low contents of macrophages and lipids, and high contents of collagen and vascular smooth muscle cells in the carotid mature plaques. In addition, CTRP9 also decreased pro-inflammatory cytokines in mature plaques. In vitro, RAW264.7 macrophages were pretreated with or without LV-CTRP9 transfection, and then stimulated with oxLDL (50 mu g/mL). We found that the expression levels of tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1) in the LV-CfRP9 group were significantly lower than those in the LV-eGFP group after exposure to oxLDL. The present data indicate that CTRP9 overexpression enhances the plaque stability in ApoE KO mice by reducing pro-inflammatory cytokines in macrophages. Our study suggests that the therapeutic approaches to enhance CTRP9 production could be valuable for plaque stabilization. (C) 2015 Elsevier Inc. All rights reserved.