Like all other members of the herpesvirus family, the closely related human herpesviruses-6 and -7 (HHV-6,7) persist in their host throughout life. In so doing, without exception, every member of the herpesvirus family has evolved mechanisms to avoid detection by the immune system. In particular, human cytomegalovirus (HCMV), mouse cytomegalovirus (MCMV), human herpesvirus-8 (HHV-8), and herpes simplex virus (HSV) all encode multiple proteins that interfere with proper MHC class I antigen presentation. The mechanisms employed by these viruses to effect removal of MHC class I from the cell surface vary. The U21 open reading frame from HHV-7 diverts class I MHC molecules to an endolysosomal compartment using an as-yet unknown mechanism. The two variants of HHV-6, HHV-6A and -6B, both possess a U21 open reading frame which contain only approximately 30% amino acid identity to the U21 sequence from HHV-7. Here we describe the characterization of the U21 gene products from HHV-6A and HHV-6B. Like HHV-7 U21, both of the HHV-6 U21 molecules bind to and divert class I MHC molecules to an endolysosomal compartment, effectively removing them from the cell surface, and providing a possible means of escape from immune detection.