Red blood cell (RBC) transfusion is unique as a common large-scale intravenous introduction of foreign tissue and provides a valuable opportunity to study human immunologic response to intravenous foreign antigen. Patients receiving RBC transfusions are at risk of forming alloantibodies against donor RBC antigens, and valid estimates of alloimmunization risk are clinically important, but little is known about the factors governing this risk or, more generally, about determinants of human response to intravenous antigen. Here, we mine large electronic patient databases enabling us to model RBC alloimmunization as a stochastic process. We identify a subgroup of transfusion recipients that has a dramatically increased risk of alloimmunization that appears to be genetically determined because it is independent of common disease states, patient age, or the number of alloantibodies already formed, and only weakly dependent on transfusion count.