The 7TM receptor, US28, encoded by human cytomegalovirus binds a broad spectrum of endogenous CC chemokines with sub-nanomolar affinity as determined in homologous competition binding assays. We here find that US28 also recognizes the membrane-associated CX₃C chemokine, fractalkine, with sub-nanomolar affinity (IC₅₀=0.42±0.09 nM). Importantly, although fractalkine could compete with high affinity against the binding of CC chemokines, the secreted CC chemokines were only able to compete for binding against radioactive fractalkine with very low affinity. It is concluded that US28, which is known to enhance cell-cell fusion processes through interaction with an as yet unidentified, human cell-specific factor, has been optimized by cytomegalovirus to selectively recognize the membrane-associated fractalkine. It is suggested that US28 expressed on the surface of infected cells and possibly on the envelope of the virion is involved in transfer of the virus from cell to cell.