BACKGROUND BK virus nephropathy (BKVN) is the major cause of transplant renal dysfunction. However, a specific antiviral agent to treat it does not exist. One therapeutic option is to reduce use of immunosuppression drugs, which can cause allograft rejection. Leflunomide has both antiviral and immunosuppressive effects, and clinical research has demonstrated its clinical efficacy against BKVN. However, a phase II randomized trial did not support this effect. Therefore, the efficacy of leflunomide remains controversial. CASE REPORT We examined 4 BKVN patients whose Cr levels stabilized with leflunomide therapy. BKVN was confirmed by a kidney biopsy 7-16 months after transplantation. The Cr levels in 3 cases continued to increase after the reduction of immunosuppression drugs, then leflunomide was administered. In 1 case, leflunomide was administered when the immunosuppression drugs were reduced. In all of the cases, mycophenolate mofetil was replaced with everolimus, and tacrolimus was replaced with cyclosporine A. The maintenance doses of leflunomide were 20 mg/day, and leflunomide was used as an antiviral agent for 3 months. In all of the cases, Cr levels and plasma BKV-PCR loads improved after the administration of leflunomide. Renal function was stable without BKVN recurrence or allograft rejection over 3 years after transplantation. CONCLUSIONS Our 4 cases show that short-term use of leflunomide during the active phase of BKVN and a combination of leflunomide and everolimus may be effective against BKVN.