Peripheral blood dendritic cells (DC) produce IFN-α in response to challenge by many enveloped viruses including herpes simplex virus (HSV) and HIV, whereas Sendai virus predominantly stimulates IFN-α production by monocytes. Glycosylated viral envelope proteins are known to be important for the induction of IFN-α. In this study we demonstrate that stimulation of IFN-α synthesis by HSV is inhibited by a number of monosaccharides, including fucose, N-acetylglucosamine, and N-acetylgalactosamine as well as the yeast polysaccharide mannan, supporting a role for lectin (s) in the IFN-α stimulation pathway. Furthermore, antiserum to the mannose receptor (MR) also inhibited HSV, vesicular stomatitis virus, and HIV-induced IFN-α production, but failed to inhibit the IFN-α induced by Sendai virus. We further demonstrated that freshly isolated blood DC and IFN-α-producing cells responding to HSV stimulation express the MR. This study therefore implicates the MR as an important receptor for the nonspecific recognition of enveloped viruses by DC and the subsequent stimulation of IFN-α production by these viruses. Thus, the MR probably serves as a critical link between innate and adaptive immunity to viruses, especially given the role of the MR in Ag capture by DC and the importance of IFN-α in shaping immunity.