CD4 is known to serve as the principal cellular receptor for HIV. However, several observations suggest that other molecules may be involved in infection of cells by HIV. Cell adhesion molecules and their ligands expressed on HIV-susceptible cells have been implicated in the biology of HIV in a number of studies. We have recently reported that HIV and SIV acquire cell adhesion molecules from host cells. We now report that a specific cell adhesion molecule, CD44, that is acquired by HIV retains its biological activity when expressed on the virus. We tested CEMx174 cells, which are CD4-positive and HIV-susceptible for phorbol ester-inducible binding to hyaluronic acid through CD44. Phorbol ester-stimulated but not unstimulated CEMx174 cells bound hyaluronic acid. Likewise, HIV from stimulated cells but not from unstimulated cells bound hyaluronic acid through acquired CD44 molecules. This is the first demonstration that adhesion molecules acquired by HIV are functional and the results imply that HIV may have the capacity to bind to any cell or substrate that its host cell binds to. The demonstration of functional adhesion receptors on HIV has important implications with respect to the tropism, infectivity, and dissemination of HIV.