Cytomegalovirus (CMV) infection is a common complication of immunosuppressive therapy after solid organ and bone marrow transplantation. In most cases, prevention and treatment with ganciclovir is successful, but in recent years the incidence of infections with CMV mutants resistant to ganciclovir has increased. Leflunomide, used as an immunosuppressive drug in rheumatic diseases, may be an effective treatment option in this setting because it also has antiviral effects. In this case report, a CMV-seronegative 60-year-old man received a kidney transplant from a CMV-seropositive donor. Post-transplant biopsy confirmed rejection and treatment with hormonal shock. CMV viremia was diagnosed 4 weeks after transplantation. The patient was treated with intravenous ganciclovir, anti-CMV immunoglobulin and continuous oral valganciclovir. Patients were transferred 6 months after transplantation and blood coded viral load confirmed symptoms of CMV infection. Treatment with double doses of ganciclovir and anti-CMV immunoglobulin did not reduce CMV viremia and therefore a diagnosis of ganciclovir-resistant cytomegalovirus infection was made. The decision was made to discontinue mycophenolic acid therapy and to start leflunomide 20 mg BID therapy. The patient received this treatment with a rapid reduction and eventual elimination of CMV viremia. Graft renal function remained stable during leflunomide treatment. Seroconversion of IgM and IgG anti-CMV was observed. Leflunomide is a reasonable option for ganciclovir-resistant CMV infection in renal transplant recipients, providing effective clearance of the virus, re-establishment of acquired immunity against cytomegalovirus, and without the additional risk of graft rejection.