Membrane cofactor protein (CD46) is a regulator of complement activation that also serves as the entry receptor for human herpes virus 6 (HHV-6) and measles virus (MV) into human cells. While it is clear that oligodendrocytes and astrocytes are cell types commonly infected by these viruses, it is unclear whether oligodendrocytes express CD46, or which are the cellular mechanisms underlying the infection. We show that adult oligodendrocytes, as well as astrocytes and microglial cells, express CD46 on the cellular surface. Moreover, we employed a quantitative fusion assay to demonstrate that HHV-6A infection of T lymphocytes enables cell–cell fusion of these cells to astrocytes or to oligodendroglial cells. This fusion is mediated by the interaction between viral glycoproteins expressed on the membrane of the infected cells and CD46 on the glial targets, and is also observed using cells expressing recombinant MV glycoproteins. These data suggest a mechanism that involves cell–cell fusion by which certain viruses could spread the infection from the periphery to the cells in the nervous system. Published 2005 Wiley-Liss, Inc.