Human herpesvirus (HHV)–7 is a ubiquitous virus that infects >90% of adults. We show that HHV-7 impairs β₂-microglobulin and human leukocyte antigen (HLA) class I and II expression in lymphoid cells in vitro. Accordingly, infected cells were more sensitive to peripheral blood natural cytotoxic activity than were uninfected cells. Analysis of β₂-microglobulin and HLA expression in biopsy specimens from human submandibular glands confirmed the ability of HHV-7 to modulate the expression of these antigens in vivo. We demonstrate that the down-modulation of HLA by HHV-7 is linked to viral replication and is not merely a consequence of the interaction of virions with the cell surface. Infected cells can therefore efficiently escape host immune pressure, which might explain the persistence of HHV-7–positive cells in several kinds of tumors and chronic infectious diseases