The receptor designated Opioid Receptor-Like 1 (ORL1) is abundantly expressed in the central nervous system (CNS) as well as by cells of the immune system. While much is known about the function of ORL1 in the CNS, there is little information in the literature about the role of ORL1 in the immune response. There have been numerous reports documenting the effects of GPCR activation on the expression of chemokines crucial in mediating inflammatory events in biological systems. The aim of the present work was to examine the effect of nociceptin administration on the pro-inflammatory chemokine expression of human monocytes. We report here that human CD14(+) monocytes expresses the mRNA for ORL1. Our results also demonstrate that nociceptin can suppress the production of CCL2/MCP-1 and CCL5/RANTES chemokine protein in both primary CD14(+) human monocytes and monocyte-like cell lines. However, nociceptin does not appear to regulate the expression of these chemokines at the level of transcription, as CCL2/MCP-1 and CCL5/RANTES mRNA levels following nociceptin treatment of monocytes were essentially normal. Although the mechanism of chemokine regulation by nociceptin is as yet unknown, it is evident that the ORL1/nociceptin system plays a role in regulating chemotactic responses of leukocytes through chemokine suppression. Finally, these data may provide the initial basis for the development of ORL1 agonists and antagonists for therapeutic treatment of inflammatory disease.