The human cytomegalovirus pUL21.5 protein is a small, secreted glycoprotein whose mRNA is packaged into virions. We demonstrate that pUL21.5 protein is a soluble CC chemokine receptor that functions as a decoy to modulate the host immune response to infection. In contrast to other viral chemokine-binding proteins, which interact promiscuously with multiple chemokines, pUL21.5 selectively binds RANTES (regulated upon activation, normal T cell expressed and secreted) with high affinity. By binding RANTES, pUL21.5 blocks RANTES interaction with its cellular receptors. We propose that human cytomegalovirus directs the synthesis of a secreted, virus-coded protein that modulates the host antiviral response even before the newly infecting viral genome becomes transcriptionally active.