Double-filtration plasmapheresis (DFPP) and splenectomy prior to transplant is used in a few centers for high-risk transplantations. We undertook a prospective study to examine the outcome of 16 kidney transplantations in crossmatch-positive patients using splenic radiation and DFPP as pretransplant immunomodification procedures. All patients received a single dose of Zenapax (50 mg intravenously [IV] 8 hours before transplant), before treatment with cyclosporine, mycophenolate mofetil, and steroids immediately posttransplant. Follow-up ranged from 3 months to 1 year. Hyperacute rejection requiring graft nephrectomy was necessary in one patient; acute rejection, which was seen in three patients, was reversed with five doses of Iort3 at 1-month posttransplant the mean creatinine was 1.3 +/- 0.6 mg/dL in patients who did not have rejection and 1.9 +/- 0.3 mg/dL in the three patients who had acute rejection. Six patients were switched from cyclosporine to sirolimus. At the end of 3 months the mean creatinine levels was 1.4 +/- 0.3 mg%. The infections included oral candida (n = 2), urinary tract infection (UTI) (n = 1), bacterial pneumonia (n = 1), and herpes zoster (n = 1). With the advent of modern immunosuppressants, pretransplant immunomodification with DFPP and splenic radiation is safe and effective. Splenic radiation is devoid of surgical risk and more acceptable to patients.