Fundamental issues remain unresolved regarding the possible contribution of viruses to vascular pathology, as well as the role of the immune system in regulating these processes. Here we demonstrate that infection of mice with γ-herpesvirus 68 (γHV68) provides a novel model for addressing these issues. Interferon-γ receptor-deficient (IFNγR(-/-)) mice died weeks to months after γHV68 infection from a severe large-vessel panarteritis. γHV68-infected B cell-deficient and normal weanling mice exhibited milder large-vessel arteritis. Immunohistochemical analyses demonstrated γHV68 antigen in arteritic lesions and revealed a striking tropism of γHV68 for smooth muscle cells. These studies demonstrate that IFN-γ is essential for control of chronic vascular pathology induced by γHV68 and suggest γ- herpesviruses as candidate etiologic agents for human vasculitis.