Two distinct human herpesvirus 6 (HHV-6) variants infect humans. HHV-6B is the etiologic agent of roseola and is associated with life-threatening neurological diseases, such as encephalitis, as well as organ transplant failure. The epidemiology and disease association for HHV-6A remain ill-defined. Specific anti-HHV-6 drugs do not exist and classic antiherpes drugs have secondary effects that are often problematic for transplant patients. Clinical trials using IFN were also performed with inconclusive results. We investigated the efficacy of type I IFN (alpha/beta) in controlling HHV-6 infection. We report that cells infected with laboratory strains and primary isolates of HHV-6B are resistant to IFN-alpha/beta antiviral actions as a result of improper IFN-stimulated gene (ISGs) expression. In contrast, HHV-6A-infected cells were responsive to IFN-alpha/beta with pronounced antiviral effects observed. Type II IFN (gamma)-signaling was unaltered in cells infected by either variant. The HHV-6B immediate-early 1 (IE1) physically interacts with STAT2 and sequestrates it to the nucleus. As a consequence, IE1B prevents the binding of ISGF3 to IFN-responsive gene promoters, resulting in ISG silencing. In comparison, HHV-6A and its associated IE1 protein displayed marginal ISG inhibitory activity relative to HHV-6B. The ISG inhibitory domain of IE1B mapped to a 41 amino acid region absent from IE1A. Transfer of this IE1B region resulted in a gain of function that conferred ISG inhibitory activity to IE1A. Our work is unique in demonstrating type I IFN signaling defects in HHV-6B-infected cells and highlights a major biological difference between HHV-6 variants.