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Cytomegaloviruses (CMVs) have a highly restricted host range as they replicate only in cells of their own or closely related species. To date, the molecular mechanisms underlying the CMV host restriction remain poorly understood. However, it has been shown that mouse cytomegalovirus (MCMV) can be adapted to human cells and that adaptation goes along with adaptive mutations in several viral genes. In this study, we identify MCMV M117 as a novel host range determinant. Mutations in this gene enable the virus to cross the species barrier and replicate in human RPE-1 cells. We show that the M117 protein is expressed with early kinetics, localizes to viral replication compartments, and contributes to the inhibition of cellular DNA synthesis. Mechanistically, M117 interacts with members of the E2F transcription factor family and induces E2F target gene expression in murine and human cells. While the N-terminal part of M117 mediates E2F interaction, the C-terminal part mediates self-interaction. Both parts are required for the activation of E2F-dependent transcription. We further show that M117 is dispensable for viral replication in cultured mouse fibroblasts and endothelial cells, but is required for colonization of mouse salivary glands in vivo. Conversely, inactivation of M117 or pharmacological inhibition of E2F facilitates MCMV replication in human RPE-1 cells, whereas replacement of M117 by adenovirus E4orf6/7, a known E2F activator, prevents it. These results indicate that E2F activation is detrimental for MCMV replication in human cells. In summary, this study identifies MCMV M117 as a novel E2F activator that functions as a host range determinant by precluding MCMV replication in human cells., Author summary Human CMV is an opportunistic pathogen causing morbidity and mortality in immunocompromised individuals. It is a highly species-specific virus that replicates only in cells from humans or chimpanzees, but not in cells from mice or other laboratory animals. Mouse cytomegalovirus (MCMV), the most commonly used model to study CMV pathogenesis in vivo, is also species-specific and does not replicate in human cells. However, the causes of the CMV host species specificity have remained largely unknown. Here we show that the viral M117 protein is a major factor contributing to the MCMV host species specificity. When M117 is inactivated, MCMV acquires the ability to replicate in human cells. We further demonstrate that M117 interacts with transcription factors of the E2F family and activates E2F-dependent gene expression. While this function is needed for MCMV dissemination in mice, it is detrimental for MCMV replication in human cells. The results of this study indicate that the host range of a virus, i.e. its ability to replicate in cells from different hosts, can depend on an appropriate regulation of transcription factors.