A patient with congenital generalized lipodystrophy developed nephrotic syndrome with progressive renal glomerulosclerosis attributed to diabetic nephropathy. Renal transplantation was performed and the patient was discharged with normal renal function. Marked hyperlipidemia (17,500 mg/dl) persisted. One month later renal malfunction developed, and an open renal biopsy was performed when there was no response to antirejection therapy. Massive lipid deposition in renal tubular cells with tubular necrosis and hemorrhage was present but only minimal evidence of graft rejection. Rejection therapy was tapered and renal function stabilized. Death occurred 2 months later because of pulmonary sepsis. Patients with generalized lipodystrophy and severe hyperlipidemia may be at an unusually high risk for renal homograft destruction.