From November 1994 to November 1997 we investigated 133 patients with alloantibodies directed against high-frequency red cell antigens (Ab-HFA). More than 90% of these antibodies were found in females. Interestingly, all carriers of anti-Lu b/8 and 7 of 13 persons with anti-Yta were pregnant women. The majority of the Ab-HFA (n = 69, 51.9%) belonged to the clinically insignificant high-titer low-avidity (HTLA) antibodies with anti-Cha as the leading specificity (n = 47, 33.8%). The remaining HTLA specificities were anti-Kna (n = 9), anti-Rga (n = 4), anti-JMH (n = 3), anti-Yka (n = 3), anti-Sda (n = 2), and anti-McCa (n = 1). In 32 additional cases (24.1%), Ab-HFA of uncertain or low clinical significance were detected: anti Yta (n = 13), anti-Lu b/8 (n = 13), anti-Coa (n = 3), anti-Ge (n = 2), one anti-AnWj.Thus, Ab-HFA of no or uncertain clinical significance achieved a proportion of roughly 75%. Clinically significant antibodies were demonstrable in 29 (22%) patients: anti-Vel (n = 14), anti-Lan (n = 5), anti-Kpb (n = 3), anti-k (n = 2), anti-Jk3 (n = 2), anti-KL (n = 1), anti-Tja (n = 1), anti-Dib (n = 1). Hemolytic transfusion reactions were noted in 6 cases (4.5%); 3 of them occurred with anti-Vel and 3 with anti-Lan. Mild hemolytic disease of the newborn was observed in one case of anti-k. Three cases remained unresolved (2%). Multiple additional red cell alloantibodies, i. e. anti-Rh, anti-K, anti-Fy and others, were present in 24 patients (18.1%) with Ab-HFA, predominantly associated with anti-Yta (57%) and anti-Cha . Most importantly, the serological reactions of Ab-HFA were weak, uniform and difficult to differentiate from nonspecific reactions. Careful serological testing with a large panel of rare test cells is necessary to distinguish the harmful from the harmless Ab-HFA.