Objective: The peptide chemerin is an emerging novel vasoconstrictor which has been implicated in altering vascular function in animal models. CMKLR1 is a known chemerin receptor which functions predominately in immune response. Chemerin has also been proposed as the ligand for orphan receptor GPR1, which our group has recently confirmed. We tested the hypothesis that chemerin was vasoactive in human vessels and identified which receptor mediated this action. Method and Results: Immunohistochemistry revealed that chemerin was expressed in endothelial cells and receptors CMKLR1 and GPR1 were expressed in the smooth muscle cells of human vessels. Quantitative PCR analysis of human vessels supported this with CMKLR1 10 fold more abundant than GPR1. C-terminal fragment chemerin149-157 (C9) caused a concentration dependent contraction in isolated endothelium denuded human saphenous vein (hSV) with a pD2=7.4±0.3 (n=4), which was shifted to the right by antagonist CCX832 (100mM), pD2=6.1±0.2 (n=3). Full characterisation of the novel antagonist CCX832 with receptor-transfected cells confirmed it to be selective for the CMKLR1 receptor, and had no effect on GPR1. In β-arrestin recruitment assays, CCX832 was functionally active at the CMKLR1 receptor causing a rightward shift of the C9 response, logKD=-8.2±0.1 (n=3); however no effect was seen at the GPR1 receptor. Radiolabelled competition binding experiments showed that CCX832 competes for binding with [125I]-C9 at the CMKLR1 receptor, pIC50=9.0±0.1 (n=5), however it does not at the GPR1 receptor. In competition binding experiments on human saphenous vein homogenate, CCX832 competes for binding with [125I]-C9, pIC50=8.6±0.4 (n=6). This is in agreement with the in vitro pharmacology data, that chemerin’s vasoactivity is mediated by CMKLR1. Data is expressed as mean±SEM. Conclusion: These data support the emerging role of chemerin as an endogenous vasoconstrictor through its receptor CMKLR1. It identifies for the first time the components of the chemerin axis in the human vasculature, and confirms that chemerin causes vasoconstriction of human vessels. This study identifies a novel therapeutic drug target for hypertension in humans.