The cardiovascular disease myocarditis is characterized by inflammation and necrosis of cardiac muscle. This disease has been associated with various viral etiologies, including cytomegalovirus (CMV). Murine CMV (MCMV) infection of adult BALB/c mice produces a disease with acute and chronic phases similar to that found in humans. In our murine model, we have investigated the therapeutic efficacy of antiviral drug administration on myocarditis. Two drugs commonly used for CMV treatment, ganciclovir and cidofovir, were subjected to trials, with both drugs showing potent antiviral activity against MCMV both in vitro and in vivo. The acute phase of myocarditis was significantly reduced when antiviral therapy commenced 24 h postinfection. Such treatment also reduced the severity of the chronic phase of myocarditis. In contrast, antiviral treatment commencing after the acute phase had no effect on chronic myocarditis. Reinfection of mice with MCMV caused exacerbation of myocardial inflammation. Such an increase in severity of myocarditis could be prevented with either ganciclovir or cidofovir treatment, but the preexisting inflammation and necrosis of the myocardium persisted. These data highlight possible therapeutic uses of antiviral drugs in viral myocarditis as well as further elucidating the pathogenic nature of the disease.