The CC chemokine receptor 8 (CCR8) is expressed on monocytes and type 2 T lymphocytes. CCR8 is the sole receptor for the human CC chemokine I-309, as well as for viral monocyte inflammatory protein-I (vMIP-I), a human chemokine homologue induced in human cells by the Kaposi sarcoma-related human herpesvirus-8. Recently it was found that I-309 messenger RNA and protein are expressed by human umbilical vein endothelial cells (HUVECs) and that the secretion of endothelial I-309 is stimulated by apolipoprotein(a). I-309, vMIP-I, and the conditioned medium from apolipoprotein(a)-stimulated HUVECs induce endothelial chemotaxis. A polyclonal anti-CCR8 antibody and a newly developed murine monoclonal antibody against CCR8 inhibited this activity. The G-protein inhibitor pertussis toxin also inhibited endothelial chemotaxis, providing further evidence for a chemokine receptor-mediated effect. Endothelial cells contain CCR8 mRNA as shown by RNA blot analysis as well by direct sequence analysis. Immunohistochemical studies identified CCR8 and I-309 on the endothelium of human atherosclerotic plaques and in endothelial-derived spindle cells of Kaposi sarcoma. These results indicate that CCR8 is an endothelial receptor that may modulate endothelial function.