Cell-membrane raft microdomains are important for successful infection by several viruses. However, their role in the cell-entry process of human herpesvirus-6 (HHV-6) is unknown. Here we tested whether HHV-6 requires cell-membrane rafts for its entry. When cell-membrane rafts were disrupted by cholesterol depletion, target-cell entry by HHV-6 was inhibited, although the virus bound normally to the cells. HHV-6 infectivity was partially rescued by adding exogenous cholesterol. Interestingly, the HHV-6 cellular receptor, CD46, was found in the rafts after virus attachment, but not in the rafts of uninfected cells, indicating that HHV-6 infection induces the re-location of its receptor into the rafts. Furthermore, glycoprotein Q1, part of a viral glycoprotein complex that binds CD46, was also associated with rafts immediately after infection. These data suggest that cellular-membrane lipid rafts are important in viral entry and that HHV-6 may enter the target cells via the rafts.