A 19-year-old woman was admitted to receive a kidney transplant from a nonliving donor. At the time of transplantation, she was taking oral phenytoin 300 mg every morning, 100 mg at noon, and 300 mg every evening (total of 700 mg/day) to treat seizures secondary to hemodialysis. Immediately after the transplantation, phenytoin treatment was resumed, and immunosuppressive therapy consisting of antithymocyte globulin, cyclosporine, mycophenolate mofetil, and corticosteroids was started. Her cyclosporine blood levels varied over the first 10 days after transplantation. Cyclosporine was discontinued, and tacrolimus was begun after acute rejection was discovered. The rejection was treated with antithymocyte globulin, plasmapheresis, and intravenous immunoglobulin, and subsequently resolved; however, the patient's blood concentrations of tacrolimus varied widely. Phenytoin is an antiepileptic drug that induces hepatic enzymes, affecting the cytochrome P450 3A family. These enzymes metabolize approximately 50% of all prescribed drugs, including cyclosporine and tacrolimus. According to the Naranjo adverse drug reaction probability scale, this patient's adverse drug reaction probably occurred from altered metabolism of cyclosporine and tacrolimus due to phenytoin therapy. Clinicians must identify drug interactions between metabolic enzyme inducers or inhibitors and drug substrates with narrow therapeutic ranges, closely monitor drug concentrations, and observe patients for clinical signs and symptoms of therapeutic failure or toxicity. In daily practice, clinicians should explore the metabolic characteristics of drugs and their biotransformation pathways to identify patients who require alternative therapy.