Herpesviruses such as cytomegaloviruses encode functions that modulate the innate response in diverse ways to counteract host sensing and delay host clearance during infection. The murine cytomegalovirus M45 protein interacts with receptor-interacting protein (RIP) 1 and RIP3 via a RIP homotypic interaction motif. Cell death suppression by M45 requires RIP homotypic interaction motif-dependent interaction with RIP1. This interaction also underlies the cell tropism role of M45 in preventing premature death of endothelial cells during murine cytomegalovirus infection. Thus, M45 is a viral inhibitor of RIP activation that provides a direct cell type-dependent replication benefit to the virus while modulating other biological processes signaling via the RIP1 adaptor such as activation of Toll-like receptor (TLR)3 as well as other mediators of cell death.