The present study was prompted by an earlier observation in this laboratory that patients with leuko-agglutinins (LA) were apt to develop transfusion reactions. It was noted that 13 of 32 patients, or 41 %, had had marked and repeated febrile transfusion reactions. In the course of other work in this area, Dausset, Goudsmith and van Loghem, Marchai et al., and Mendes de Leon all called attention to the susceptibility of patients with LA to febrile transfusion reactions. To both confirm and extend the view that LA might be a significant factor in the etiology of the unexplained febrile transfusion reaction, we have pursued three lines of investigation. First, a group of sera from patients with transfusion reactions were examined for LA; second, patients receiving repeated transfusion therapy were followed for the development of both transfusion reactions and LA; and third, to determine if a febrile reaction could be prevented, these patients were treated with blood from which the majority of leukocytes had been removed.