FTY720, a novel immunomodulator, causes rapid temporary depletion of peripheral-blood lymphocytes, inducing their sequestration in secondary lymphoid organs. FTY720 is effective in animal models of transplantation and is under evaluation for use in human transplantation. We report a 48-year-old renal transplant recipient who developed acute antibody-mediated rejection under a high-dose FTY720 (5 mg/d), low-dose cyclosporine A, and prednisone treatment protocol. A T-cell antihuman globulin and National Institutes of Health extended B-cell cross-match with donor cells were negative before transplantation. At 10 weeks posttransplantation, serum creatinine level increased and a renal biopsy showed a striking interstitial CD68(+) monocyte/macrophage infiltration with C4d staining of peritubular capillaries. Flow panel reactive antibody levels were positive in the recipient's serum for class I (9%) and class II (75%). The positive panel reactive antibody levels and presence of C4d in peritubular capillaries justified the diagnosis of antibody-mediated rejection. However, the presence of macrophage-rich interstitial infiltrate suggested a contribution of cellular rejection. The morphological characteristic of rejection with a striking interstitial CD68(+) monocyte/macrophage infiltration with paucity of T cells is very unusual and may reflect a unique effect of FTY720 therapy.