Blood transfusion, the main therapy for patients with severe thalassemia, is challenged by alloantibodies that can lead to hemolytic transfusion reactions. The use of prophylactic antigen-matched units is recommended, but serologic typing, before the first transfusion, is rarely performed and is not reliable after chronic transfusion. Patient DNA-based typing is a promising strategy, but clinical outcome data are lacking. The aim of this study was to determine the benefits of antigenmatched transfusion guided by DNA-based typing in terms of new alloantibody formation and increases in mean pretransfusion hemoglobin (Hb) levels. We performed DNA-based typing on samples from 24 transfusion-dependent patients with thalassemia who had no serologic phenotyping performed before the first transfusion. These patients were then transfused with antigen-matched donor RBC units that were typed serologically. New alloantibody formation and mean pre-transfusion Hb levels were evaluated after implementing this extended common antigen-matching transfusion protocol. Sixty-three percent of the patients in this study were diagnosed as having beta-thalassemia Hb E. Alloantibodies were already present in 87.5 percent (21/24) of these patients, and most of these antibodies were multiple and/ or unidentified. After the enrollment, there were 717 transfusion episodes comprising 1209 RBC units. The number of RBC units transfused to each patient ranged from 22 to 119 units. At the median duration of 25.5 months (range 10-34 months), no new alloantibodies were detected since the beginning of the protocol. Seventy-four transfusion episodes in six patients were crossmatch-positive due to autoantibodies (patients 2, 4, 8, 9, and 14) or anti-Chido (patient 18) that had been identified before the study. There were no hemolytic transfusion reactions in this study. Five patients (patients 1, 2, 12, 15, and 20) showed increased mean pre-transfusion Hb levels (≥1 g/dL) and one patient (patient 16) had longer intervals between transfusions (compared with those before the protocol), suggesting longer RBC survival, although there was no statistical difference in the whole group. Our study highlights the benefits of DNA-based typing in chronically transfused patients with thalassemia who had no phenotyping data before the first transfusion. Patient DNA-based typing for antigen-matched transfusion is safe in thalassemia and allows us to obtain better-matched blood units for complicated patients.