Background. Traditionally, single-unit red blood cell (RBC) transfusions were believed to be insufficient to treat anemia, but recent data suggest that they may lead to a safe reduction of transfusion requirements. We tested this hypothesis by changing from double- to single-unit RBC transfusion policy. Design and Methods. We performed a retrospective cohort study in patients with hematological malignancies receiving intensive chemotherapy or hematopoietic stem cell transplantation. The major endpoints were the reduction in the total number of RBC units per therapy cycle and per day of aplasia. The study comprised 139 patients receiving 272 therapy cycles. A total of 2212 RBC units were administered in 1548 transfusions. Results and conclusions. During the double- and single-unit period one RBC unit was transfused in 25% and 84% of the cases and the median number of RBC units per transfusions was 2 and 1, respectively. Single-unit transfusion led to a 25% reduction of the RBC requirements per therapy cycle and 24% per aplasia day, but was not associated with a higher outpatient transfusion frequency. In multivariate analysis, single-unit transfusion resulted in reduction of 2.7 RBC units per treatment cycle (p=0.001). The pretransfusion hemoglobin levels were lower during the single-unit period (median 61g/L vs. 64g/L) and more transfusions were administered in patients with hemoglobin values ≤60gl/L (47% vs. 26%). Neither more severe bleedings nor platelet transfusions were recorded during the single-unit period and the overall survival was similar in both cohorts. Conclusions. Implementing a single-unit transfusion policy saves 25% of RBC units and thereby reduces the risks associated with allogeneic blood transfusions.