Human cytomegalovirus (HCMV) is a ubiquitous pathogen that persists in the host and can cause severe disease in the immunocompromised individual or in the fetus. Analysis of the nucleotide sequence of the virus genome has revealed the presence of an open reading frame whose predicted translation product has homology with the heavy chain of the major histocompatibility complex (MHC) class I molecule of higher eukaryotes, and the observed sequence homology was given additional significance by the independent observation that HCMV virions can bind beta 2 microglobulin (beta 2m), the light chain of the MHC class I molecule. We expressed both the HCMV class I homologue and the human beta 2m gene in recombinant vaccinia viruses. We show that the coexpressed gene products associate, that the transport of beta 2m to the cell surface is dependent on coexpression of the class I homologue and that the viral gene product is therefore functionally related to its cellular counterpart. We observe also that, in HCMV-infected cells, no synthesis of mature cellular class I molecules occurs, while messenger RNA levels remain unaltered, and we speculate that one function of the viral homologue may be to sequester beta 2m, thus preventing the maturation of cellular class I molecules and rendering the infected cell unrecognizable by cytotoxic T cells.