DC-SIGN expressed on dendritic cells (DCs) efficiently binds and transmits various pathogens, including human immunodeficiency virus, to lymphoid tissues and permissive cells. Consequently, alteration of DC-SIGN expression may affect susceptibility and resistance to pathogens. The present study shows that infection with human herpesvirus 6 (HHV-6) induces downregulation of DC-SIGN expression on immature DCs. Expression levels of DC-SIGN mRNA and intracellular protein appeared to decrease following infection with HHV-6, indicating that downregulation of surface DC-SIGN occurs at the transcriptional level. Downregulation of DC-SIGN was not induced by inoculation of UV-inactivated HHV-6 or culture supernatant of HHV-6-infected DCs, indicating that replication of HHV-6 in DCs is required for downregulation of DC-SIGN. The present study demonstrates for the first time that expression of DC-SIGN is altered at the transcriptional level by virus infection.