We demonstrate that the novel immunosuppressive agent mycophenolate mofetil (MMF), that has been approved for use in kidney transplant recipients, strongly potentiates the antiviral activity of acyclovir in murine models for herpesvirus infections. Hairless mice that were infected intracutaneously with herpes simplex virus type 1 were treated systemically with ACV (20 mg/kg per day) and topically with 5% MMF. Combined use of both drugs resulted in an almost complete protection, whereas single use of either compound had virtually no effect. When athymic-nude mice were infected with an ACV-resistant (ACVr)-thymidine kinase-deficient (TK-) HSV-2 strain, combined use of systemically administered ACV (100 mg/kg per day) and topically applied MMF (5%) protected 60% of the animals against the infection, whereas all mice treated with either drug alone succumbed. Since transplant recipients under MMF therapy may develop opportunistic herpesvirus infections, requiring treatment with acyclovir (or valaciclovir), our findings have important implications for the treatment of these herpesvirus infections.