Nine unexpected antibodies of unquestioned clinical significance were detected when the major crossmatch was performed on 31,320 pretransfusion blood samples from 8969 patients whose screening test for unexpected antibodies was nonreactive. Three of the antibodies retrospectively were found to manifest a positive screening test. Another antibody was not detected by the antibody screening test due to an error in preparation of the screening red blood cells. The overriding importance of the major crossmatch is the assurance of ABO compatibility between donor blood and recipient. Therefore, while this study does not resolve whether the antiglobulin phase of the procedure might be considered optional, the major crossmatch should not be eliminated.