Outlined is the background and rationale for the initiation of a randomized prospective platelet transfusion trial to evaluate the effects of platelet dose on hemostasis and platelet utilization rates. This clinical trial is being performed by the newly established Transfusion Medicine/Hemostasis Clinical Trial Network supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. The trial will randomize 1,350 patients into three platelet transfusion arms based on body surface area (BSA). The lower dose will be 1.1 × 1011 platelets/m2, the medium dose will be 2.2 × 1011 platelets/m2, and the higher dose will be 4.4 × 1011 platelets/m2. The primary outcome measure will be the incidence of Grade 2 bleeding; i.e., gross hemorrhage without the need for red cell transfusion. Major secondary outcome measures will be the total number of platelets transfused, the total number of platelet transfusion events, the highest grade of bleeding, and bleeding severity. It is expected that this clinical trial will change platelet transfusion practice by identifying whether low-dose platelet transfusion therapy provides adequate hemostasis and what is the most cost-effective strategy for providing platelet transfusions. J. Clin. Apheresis 21: 78–84, 2006. © 2006 Wiley-Liss, Inc.