Several γ-herpesviruses encode homologs of host regulators of complement activation (RCA) proteins, suggesting that they have evolved immune evasion strategies targeting complement. We evaluated the role of complement factor C3 (C3) and the murine γ-herpesvirus 68 (γHV68) RCA protein in viral pathogenesis. Deletion of the γHV68 RCA protein decreased virulence during acute CNS infection, and this attenuation was specifically reversed by deletion of host C3. The γHV68 RCA protein was also important for persistent viral replication and virulence in IFNγR-/- mice. In addition, C3 played a role in regulating latency, but this was not counteracted by the γHV68 RCA protein. We conclude that complement is a key host defense against γ-herpesvirus infection and that γ-herpesviruses have evolved an immune evasion strategy that is effective against complement-mediated antiviral responses during acute but not latent infection.