Preformed anti-HLA antibodies due to previous kidney transplantation, reported as pannel reactive antibodies (PRA), prolong patients waiting time for kidney transplantation. Combined plasma exchange (PE), cyclophosphamide and alemtuzumab can safly and persistently convert the positive donor-specific crossmatch to negative via depletion of T and B lymphocytes as well as amilioration of the immunogenic nature of the newly formed cells. Twenty one CRF patients waiting for their second kidney transplantation having 100% positive PRA for class I and 7-54% positive PRA for class II together with repeated positive donor-specific crossmatch for total alogenic lymphocytes at differrent tempratures. Three every other day sessions of 2 liters of plasmapheresis and one gram of cyclophosphamide after the first session only and 150 mg/kg of intravenous immunoglobulins (IVIG) after every session of PE. A fourth PE session followed by IVIG and 20 mg of alemtuzumab just before the operation and another 20 mg of alemtuzumab on day one postoperatively. Immunologic selection criteria included that the new donor should have the same matched DR allel of the previous donor and to avoid all class I antigens as well as the mismatched DR of both recipient and donor for all cases. Immunosuppressive protocol included cyclosporine, MMF and steroids. No appreciable changes in PRA was noticed in all patients but donor-specific anti-HLA antibodies class I and calss II converted to negative at differrent tempratures. Crossmatch at days zero, 7,30 and 100 were all negative in all patients. Serum creatinine at day zero, 7,30 and 100 were 7.4, 1.94, 1.14 and 1.12 mg/dl respectivly. Total lymphocytic count at days zero, 7,30 and 100 were 7.3%, 8.4%, 10.3% and 10.6% respectivly. No graft losses,no serious infections and their postoperative events were smooth. PRA role in second kidney transplantation is overestimated. Plasma exckange and the combination of IVIG, cyclophosphamide and alemtuzumab can safly and persistently deplete and amiliorate the immunogenic nature of the newly formed lymphocytes.