The major crossmatch must include an anti-human globulin test, unless the transfusion recipient has no apparent significant unexpected antibodies, in which case the use of only an immediate spin crossmatch method is considered acceptable. However, a minority of laboratories utilize only an immediate spin crossmatch as their routine major crossmatch, possibly because contemporary antibody screening tests occasionally miss detecting some unexpected antibodies, and these missed antibodies are more often detected by the anti-human globulin crossmatch than by the immediate spin crossmatch. In the present study, 20 hospitals were surveyed to determine how often an acute hemolytic transfusion reaction would occur when only an immediate spin crossmatch was used as the major crossmatch method. During the study period, 1.3 million immediate spin crossmatches were performed, and five patients experienced acute overt hemolytic transfusion reactions that were believed to be caused by antibodies that were missed by both the antibody screening test and immediate spin crossmatch (one hemolytic event per 250,000 immediate spin crossmatches). The implicated antibodies were anti-Jka, anti-Wra, anti-C, anti-c, and anti-Kpa. These survey data demonstrate that the routine crossmatching of blood using an immediate spin crossmatch may rarely result in an acute hemolytic transfusion reaction if the antibody screening cells used during pretransfusion compatibility testing fail to detect some clinically significant red blood cell antibodies.