Many modern therapies depend on platelet (PLT) transfusion support. PLTs have a 4- to 7-day shelf life and are frequently in short supply. In order to optimize the inventory PLTs are often transfused to adults without regard for ABO compatibility. Hemolytic reactions are infrequent despite the presence of ‘high titer' anti-A and anti-B antibodies in some of the units. Despite the low risk for hemolysis, some centers provide only ABO identical PLTs to their recipients; this practice might have other beneficial outcomes that remain to be proven. Strategies to mitigate the risk of hemolysis and the clinical and laboratory outcomes following ABO-matched and mismatched transfusions will be discussed. Although the PLTs themselves do not carry the D antigen, a small number of RBCs are also transfused with every PLT dose. The quantity of RBCs varies by the type of PLT preparation, and even a small quantity of D+ RBCs can alloimmunize a susceptible D- host. Thus PLT units are labeled as D+/-, and most transfusion services try to prevent the transfusion of D+ PLTs to D- females of childbearing age. A similar policy for patients with hematological diseases is controversial, and the elements and mechanisms of anti-D alloimmunization will be discussed.