While a number of studies have demonstrated that human Mx proteins can inhibit particular herpesvirusesin vitro, we are the first to report the antiviral activity of mouse Mx1 (mMx1) against alphaherpesviruses bothin vitroandin vivo. We demonstrate that both overexpressed mMx1 and endogenous mMx1 potently restrict HSV-1 growthin vitro. mMx1-mediated inhibition of HSV-1 was not associated with inhibition of virus entry and/or import of the viral genome into the nucleus, but rather with inhibition of HSV-1 genomic replication as well as subsequent late gene expression.