Mild-to-profound anemia, thrombocytopenia, and rarely neutropenia have been observed in patients with the acquired immune deficiency syndrome (AIDS). To investigate a possible immune mechanism, blood samples from 28 hospitalized AIDS patients, four asymptomatic homosexual men, four homosexual men with the AIDS-related lymphadenopathy syndrome, 30 hospitalized patients with diseases other than AIDS, and 60 blood donors were tested for the presence of atypical red cell antibodies. Eighteen AIDS patients (64%) had anti-i, nine (32%) had autoanti-U, and 12 (43%) had a positive direct antiglobulin test. One asymptomatic homosexual man and three homosexual men with lymphadenopathy also had anti-i. In contrast, of the 30 patients with diseases other than AIDS and 60 donors, none had anti-U or a positive direct antiglobulin test. One patient with sickle cell disease had anti-i. The mean hemoglobin level of AIDS patients with anti-i or anti-U was significantly lower than the mean hemoglobin level of patients who did not have those antibodies.