The soluble form of the Respiratory Syncytial Virus (RSV) G protein (sG) bears resemblance to the chemokine fractalkine (CX?CL1). Both RSV sG and CX3CL1 possess a mucin-like domain and a CX3C motif, exist in membrane-associated and soluble forms, and bind to the CX?CR1 receptor expressed on immune and epithelial cells. To explore the biological significance of RSV sG and CX?CR1 interaction, we produced wild type (WT) and CX?C motif-deficient (CX3CMut) RSV sG proteins and determined their effects on CX?CR1 signaling in monocytic cells. Both CX3CMut- and WT RSV sG failed to activate CX?CR1 signaling directly. However, WT sG competed with CX?CL1 for CX?CR1 binding and reduced CX3CL1-induced CX?CR1-activation, monocyte migration, and adhesion. The CX?C motif of sG was crucial for competitive blocking of CX3CL1-mediated activation, as CX?CMut sG did not affect these CX?CR1 functions significantly. Thus, blockade of CX?CR1 signaling by sG may allow RSV to dampen host immune responses.