Type I interferons (IFNs) are innate cytokines with potent antiviral and immunoregulatory activities. It remains unclear how human cytomegalovirus (HCMV) can establish persistence in the face of these strongly antagonistic cytokines. In this study, we confirm that IFN-α efficiently suppresses the penetration of HCMV into susceptible cells, including monocytes, the major cell population in peripheral blood that is highly susceptible to HCMV infection. We further demonstrate that the HCMV-derived interleukin 10 (IL-10) homolog functions similar to cellular IL-10 and broadly inhibits TLR-induced transcriptional activation of IFN-α/β genes in plasmacytoid dendritic cells (PDCs), a major type I IFN-producer in vivo that is highly resistant to HCMV infection in vitro. These results suggest that HCMV subverts innate immunity by suppressing type I IFN production of PDCs during primary viral infection via its IL-10 homolog.