Some patients' sera react with all available donors' red cells and a compatible donor is difficult or impossible to be found. These may either be due to a complex mixture of antibodies or the presence of alloantibodies against high-frequency antigens (HFAs). The aim of this study is to identify the prevalence and characteristics of antibodies to HFAs in Saudi Arabian patients. A total of 23 out of 172 000 patients who received blood transfusions had rare alloantibodies to HFAs at an incidence of 0.013%. Twenty-three patients suspected with pan-reactive alloantibodies against HFAs had their red cells tested using antisera to HFAs, while their plasma was tested against a selected panel of red blood cells with rare phenotypes. Anti-Ge2 antibody was found in the highest number of patients (56.5%), whereas anti-U, anti JK3, anti H, anti-RH 29, anti-hr s , anti-Kn a , anti-Ch, anti-Rg, anti-Yt a , and anti-Cr a antibodies were found in the remaining patients (43.5%). This study suggests that although antibodies such as anti-Ge2, anti-Kn a , anti-Ch, anti-Rg, anti-Yt a , and anti-Cr a are not clinically significant, they cause a delay in the provision of compatible blood. Whereas, anti-U, anti JK3, anti H, anti-RH29 and anti-hr s are clinically significant antibodies. An understanding of antibody characteristics to HFAs and the widespread use of the extended red cell phenotype and antibody identification panel will both be helpful for the diagnosis of these HFAs.