Chemerin is a chemotactic protein that binds to the G protein – coupled receptor, ChemR23. We demonstrate that murine chemerin possesses potent antiinfl ammatory properties that are absolutely dependent on proteolytic processing. A series of peptides was designed, and only those identical to specifi c C-terminal chemerin sequences exerted antiinfl ammatory effects at picomolar concentrations in vitro. One of these, chemerin15 (C15; A 140 -A 154 ), inhibited macrophage (Mϕ) activation to a similar extent as proteolyzed chemerin, but exhibited reduced activity as a Mϕ chemoattractant. Intraperitoneal administration of C15 (0.32 ng/kg) to mice before zymosan challenge conferred signifi cant protection against zymosan-induced peritonitis, suppressing neutrophil (63%) and monocyte (62%) recruitment with a concomitant reduction in proinfl ammatory mediator expression. Importantly, C15 was unable to ameliorate zymosan-induced peritonitis in ChemR23 –/–mice, demonstrating that C15 ’ s antiinfl ammatory effects are entirely ChemR23 dependent. In addition, administration of neutralizing anti-chemerin antibody before zymosan challenge resulted in a signifi cant exacerbation of peritoneal infl ammation (up to 170%), suggesting an important endogenous antiinfl ammatory role for chemerin-derived species. Collectively, these results show that chemerin-derived peptides may represent a novel therapeutic strategy for the treatment of infl ammatory diseases through ChemR23.