Human cytomegalovirus (CMV) infection results in pneumonitis in bone-marrow and lung-transplant recipients. The source of CMV infection contributing to the onset of pneumonitis is unclear, but may involve infection of the lung endothelium in the presence of infiltrating mononuclear cells. Viral infection stimulates the host cell to express chemokines as signals to recruit specific immune cells to the site of injury. CMV encodes a chemokine receptor that may function to reduce host cell expression of chemokines. In the study reported here we found that extracellular concentrations of the chemokine regulated on activation, normal T cell expressed and secreted (RANTES) are depleted during productive infection of primary endothelial cells with CMV strain 4010, an endothelial-adapted strain of CMV. Utilizing adenovirus-transformed human kidney epithelial cells (type 293 cells) that stably express the CMV-encoded chemokine receptor US28, we found that depletion of extracellular RANTES during infection is attributable to US28, which binds and internalizes extracellular RANTES.