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Leflunomide is an experimental immunosuppressive agent that has shown efficacy as an antiviral agent against human cytomegalovirus (HCMV) and polyomavirus strain BK (BKV). An antiviral regimen has been approved for immunosuppressed patients suffering complications from HCMV infection, whereas a good treatment option for patients infected with BKV does not exist. Unfortunately, the antiviral treatment options for patients infected with HCMV have helped promote the propagation of multi-drug resistant HCMV strains. New antiviral treatment options must be developed to ensure the health of immunosuppressed patients suffering from HCMV and BKV infection. This body of work illustrates the possible antiviral mechanisms associated with Leflunomide using an in vitro model system. We have tested the hypothesis that the antiviral activity of A77 1726, the active metabolite of Leflunomide, is a result of its inhibition of phosphorylation of one or more viral structural proteins. Western blot, Southern (Dot Blot) blot, and CMV gene array analysis demonstrated that Leflunomide does not inhibit HCMV DNA synthesis, the translation of essential viral proteins, or th