Ata is a high-frequency red blood cell (RBC) antigen. Anti-At(a) has been reported in rare At(a-) black subjects. We report two cases of anti-At(a). A clinically significant anti-At(a) was found in a 26-year-old black woman with systemic lupus erythematosus. The patient had a transfusion reaction with chills and nausea during a RBC survival study, and 95% of the radiolabeled At(a+) RBCs were destroyed within 3 h. A concurrently performed monocyte monolayer assay was strongly reactive. Anti-At(a) thus can cause rapid hemolysis of transfused RBCs, but At(a-) donor units are extremely scarce in rare donor registries. A second patient at our hospital had anti-At(a) which did not affect her newborn. She also had autoimmune disease, insulin-dependent diabetes mellitus.