Dr. Gilbert H. Mudge: In this clinic we have discussed the human blood groups in terms of fundamental biologic mechanisms and also in relation to the many clinical problems associated with transfusions. The antigenic composition of erythrocytes has been described with emphasis upon the genetic and immunologic aspects. The various factors are inherited in accordance with mendelian principles but the different systems are independently transmitted without cross-linkage. Problems of determining an individual's phenotype, as well as genotype, are discussed, not only in relation to genetic studies but also in terms of the identification of rare blood groups of both donors and recipients. The major blood groups, the Rh system and the less common factors are described in terms of the special problems which each presents. The identification of blood group factors by immunologic technics depends on two different types of antibodies, the saline agglutinins and the so-called blocking antibodies. Some of the special methods for their detection are outlined. The experimental evidence is reviewed which indicates that the arrangement of antigens on the red cell surface may be an important factor in determining the manifestations of the antigen-antibody reaction. Some of the problems peculiar to the identification of unusual antibodies are discussed. As an example, recent work is presented on the definitive identification of an autoantibody in a patient with hemolytic anemia. The fundamental question—why does an individual not form antibodies to antigens in his own tissues?—is also discussed in terms of some new observations on blood groups. Several instances of human blood group chimeras have been recently described. These individuals possess two different sets of erythrocytes which have apparently developed independently of each other. This phenomenon has been extensively studied in cattle, in which it is common, and is attributed to the intrauterine admixture of blood between the circulation of non-identical twins. The striking feature of this phenomenon is the individual's subsequent failure to produce antibodies to red cells which are essentially of foreign origin. This may be related to the recently reported finding that animals fail to develop antibodies to other antigens when the latter are administered early in the course of intrauterine development. These observations have enormous implications for many immunologic problems. The occurrence of hemolytic transfusion reactions is determined by the frequency of the several blood group factors in the general population, by variations in the antigenicity of the different factors, and by the destructive capacity of the antibody in question. Different types of hemolytic reactions can be correlated with the rate of red blood cell destruction by the isoantibody. The mechanism of the erythrocyte destruction appears to involve lysis, phagocytosis and agglutination. However, additional mechanisms have been implicated by experimental studies in the dog. In some of these reactions, the rate of red cell destruction is quantitatively related to the levels of antibody and of complement in the recipient's circulation. A major contribution from the experimental transfusion reaction is the demonstration that the increased rate of erythrocyte destruction in vivo is due to antibodies, even though such antibodies cannot be demonstrated by in vitro tests. Many practical problems associated with the management of transfusion reactions are discussed, and procedures are outlined for their careful investigation. Problems posed by the so-called “dangerous universal donors” are also described in detail. In summarizing the severe reactions which occur following the transfusion of human blood, it is disheartening to note that most of these are not caused by inadequate scientific knowledge but are in fact directly attributable to human errors. Such a conclusion warrants emphasis.