Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that causes birth defects in newborns and severe disease in immunocompromised individuals. The broad tropism of HCMV infection suggests that it uses multiple receptors. We recently showed that the epidermal growth factor receptor (EGFR) serves as a receptor for HCMV. Here we show that HCMV also uses integrin alphavbeta3 as a coreceptor. Upon infection, HCMV glycoproteins gB and gH independently bind to EGFR and alphavbeta3, respectively, to initiate viral entry and signaling. Alphavbeta3 then translocates to lipid rafts where it interacts with EGFR to induce coordinated signaling. The coordination between EGFR and alphavbeta3 is essential for the early events of HCMV infection, including viral entry, RhoA downregulation, stress-fiber disassembly and viral nuclear trafficking. Our findings support a model in which EGFR and alphavbeta3 work together as coreceptors for HCMV entry and signaling. This discovery is fundamental to understanding HCMV pathogenesis and developing treatment strategies targeted to viral receptors.