The majority of acute infection-associated hemolytic diseases of infancy and childhood have been suggested to be caused by exogenic alterations of the erythrocyte surface, though laboratory methods for their further evaluation were not yet available. Investigating 96 children, the present study characterizes 72% of cases as corresponding to this type of acute acquired hemolytic anemia, which cannot be clearly related to autoantibodies against unmodified components of the host's own red cells. Using a new immunofluorescence test, the erythrocyte membrane of 80% of these children was found to be altered in vivo by nonspecific adsorption of foreign material released from the infectious micro-organisms. In 24% of cases additive binding of complement was detectable by an antiglobulin test. Thus, the adsorption of microbial antigens to the red cell surface is suggested to be one of the causes for the removal of altered erythrocytes due to phagocytosis or a complement-dependent destruction during the course of infection-associated hemolytic anemia. Especially in childhood, the immunofluorescent detection of an erythrocyte sensitization in vivo provides a further characterization of this type of mostly transient hemolytic disease, which probably can be treated without any immunosuppressive drug, merely by elimination of the underlying infection.