It has been shown that herpes simplex virus type 1 (HSV-1) blocks specific immune responses by various mechanisms. Cell lines infected with HSV-1 for instance show a severe impairment of the interferon-gamma (IFN-gamma)-induced signal transducer and activator of transcription 1 (STAT1) signaling pathway. Thus, we examined the influence of HSV-1 infection on IFN-gamma signal transduction in mature dendritic cells (mDCs). In this study, we report the down-regulation of the IFN-gamma receptor alpha chain (IFNGR1) at the mRNA level in HSV-1 infected mDCs. As a consequence, the expression of the IFNGR1 subunit on the cell surface of the infected cell was strongly reduced. Furthermore, we were able to show the inhibition of STAT1 phosphorylation following HSV-1 infection in mDCs, while protein levels of STAT1 remained constant. As a direct downstream effect of STAT1 phosphorylation, the activation of the transcription factor IRF-1 was also clearly inhibited and could no longer be induced by the addition of IFN-gamma. Additional experiments using a virus strain lacking the vhs gene suggested that the mutant virus is more sensitive to IFN-gamma as STAT1 signaling was inhibited to a lesser extent. Infection with a UV-inactivated, replication incompetent virus did not influence the STAT1 signaling pathway at all. In conclusion, we show that HSV-1 blocks IFN-gamma signaling in mDCs, which requires viral gene expression and involves the viral protein vhs.