BackgroundCD59 is a cell surface glycoprotein of approximately 20 kDa limiting the lytic activity of the terminal complement complex C5b‐9. Although CD59 is known as a red blood cell (RBC) antigen defined by monoclonal antibodies, it so far has not been identified as a blood group antigen, since the description of a human alloantibody was missing. In this study we show the presence of an anti‐CD59 in a patient affected by a homozygous CD59 deficiency.Study Design and MethodsRBC CD59 and CD55 were determined by flow cytometry or by the column agglutination technique using monoclonal antisera. Commercially available His‐tagged recombinant soluble CD59 protein was used to inhibit anti‐CD59.ResultsSeven cases of an isolated CD59 deficiency due to three distinct null alleles of the CD59 gene have been published so far. Recently we described the CD59‐null allele c.146delA in a young child of heterozygous parents. Her plasma contained an alloantibody directed against the high‐prevalence RBC antigen CD59. The antibody specificity was identified using soluble recombinant human CD59 protein, which blocked the reactivity of the patient's antibody and of monoclonal anti‐CD59 but not of monoclonal anti‐CD55. In addition, RBC alloantibodies such as anti‐K, anti‐C, anti‐c, or anti‐Fya remained unaffected. Therefore, inhibition by recombinant CD59 is a useful diagnostic tool to detect alloantibodies in the presence of anti‐CD59.ConclusionThis is the first demonstration of a human anti‐CD59 alloantibody, which defines CD59 as an RBC blood group antigen. CD59 represents a candidate for a new blood group system.