Cytomegaloviruses (CMVs) establish persistent, systemic infections of immunocompetent hosts. Their evasion of CD8⁺ T cells is well known. The myeloid cells that CMVs colonize can also potentially interact with CD4⁺ T cells via MHC class II (MHC II). Human CMV attacks the MHC II presentation pathway in vitro, but how CD4⁺ T cell evasion contributes to host colonization is unknown. CMV infections long pre-date the divergence of primates from rodents, and Murine CMV (MCMV) is likely to have a similar need for evasion. It down-regulated MHC II via M78, a 7 transmembrane domain viral protein that captured MHC II from the cell surface for degradation in lysosomes. M78-deficient MCMV failed to down-regulate MHC II, and after nasal inoculation showed a defect in salivary gland colonization that was significantly rescued by CD4⁺ T cell loss. Therefore MCMV requires CD4⁺ T cell evasion to colonize its main site of long-term shedding.