It can be impossible to identify compatible platelet donors for alloimmunized patients whose HLA type cannot be determined or who have uncommon HLA types. We have previously shown that histocompatible donors can be rapidly identified by “mass screening” of platelet concentrates (PC), which are readily available in all blood banks, using a solid-phase adherence platelet cross-matching technique. Compatible PC were given to five alloimmunized patients with multispecific HLA antibodies refractory to random donor (RD) PC and selected single-donor platelet transfusions. After transfusions which produced satisfactory responses, we identified the original whole blood donors to serve as apheresis donors. Thus, the donors selected were compatible in vitro by cross-matching, and in vivo by transfusion. Only 3% to 13% of PC cross-matched for these alloimmunized patients were potentially compatible and it was necessary to screen large numbers (65 to 205 U) of PC per patient. Eighteen of 22 PC-selected transfusions produced satisfactory increments, allowing selection of 12 donors, all of whom were willing to undergo apheresis. Ten of 12 of these single- donor transfusions were successful; the two unsuccessful transfusions were infused 2 weeks after the initial PC cross-match and were still compatible with the original serum, but incompatible with more recent serum, demonstrating a change in antibody reactivity. The HLA types of the successful single donors selected by PC cross-matching differed widely from the patients' HLA types and, therefore, these donors would not have been selected by standard approaches using HLA typing. Cross- matching large numbers of RD PC for the identification of apheresis donors is helpful in the management of the alloimmunized patient and may be of particular utility for blood centers that do not have access to HLA-typed donor pools.