We have cloned a human cDNA for a novel CC chemokine receptor (CC CKR) designated CC CKR5 that has 48–75% amino acid identity to other CC CKRs. CC CKR5 mRNA was detected constitutively in primary adherent monocytes but not in primary neutrophils or eosinophils. Macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and RANTES were all potent agonists for CC CKR5 (EC50 = 3–30 nM) when calcium flux was measured in transfected HEK 293 cells, yet the apparent binding affinities of the corresponding iodinated chemokines to intact cells expressing the receptor were low (IC₅₀ ~100 nM). The calcium flux responses were completely blocked by treatment of transfected cells with pertussis toxin. These data suggest that CC CKR5 is a G_i-coupled receptor that may mediate monocyte responses to MIP-1α, MIP-1β, and RANTES.