Acute lung injury (ALI) is an infrequently recognized complication of transfusion therapy. Although the role of passive transfer of leukoagglutinating antibodies has been acknowledged, there is little documentation of the relationship of these antibodies in transfused blood to the human leukocyte antigen (HLA) phenotype of the recipient. Recently, we observed 5 cases of transfusion-related ALI, and in all cases leukoagglutinating and lymphocytotoxic antibodies were found in serums of the transfused blood products. In 3 cases, the antibodies corresponded to the HLA antigens of the recipient. Multiparous blood donors whose plasma contains these antibodies represent a potential transfusion hazard. It is recommended that blood component usage from donors implicated in these reactions be restricted to frozen or washed red blood cells. The incidence of leukoagglutinin-associated ALI may be more frequent than previously appreciated. Current concepts of the mechanism of microvascular pulmonary injury are discussed in relation to these cases.