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Complement-mediated autoimmune hemolytic anemia (CM-AIHA) is characterized by destruction of red blood cells (RBCs) by autoantibodies that activate the classical complement pathway. These antibodies also reduce transfusion efficacy via lysis of donor RBCs. Since C1-inhibitor (C1-INH) is an endogenous regulator of the classical complement pathway, we hypothesized that peritransfusional C1-INH in patients with severe CM-AIHA reduces complement activation and hemolysis, and thus enhance RBC transfusion efficacy. We conducted a prospective, single center, phase 2 open-label trial (EudraCT2012-003710-13). Patients with confirmed CM-AIHA and indication for the transfusion of two RBC units were eligible for inclusion. Four intravenous C1-INH doses (6000, 3000, 2000 and 1000 U) were given with 12 h intervals around RBC transfusion. Serial blood samples were analyzed for hemolytic activity, RBC opsonization, complement activation and inflammation markers. Ten patients were included in the study. C1-INH administration increased plasma C1-INH antigen and -activity, peaking at 48 h after the first dose, accompanied by a significant reduction of RBC C3d deposition. Hemoglobin levels increased briefly after transfusion but returned to baseline within 48 h. Overall, markers of hemolysis, inflammation and complement activation remained unchanged. Five grade 3 and one grade 4 adverse event occurred, but were considered unrelated to the study medication. In conclusion, peritransfusional C1-INH temporarily reduced complement activation. However, C1-INH failed to halt hemolytic activity in severe transfusion-dependent CM-AIHA. We cannot exclude that posttransfusional hemolytic activity would have been even higher without C1-INH. The potential of complement inhibition on transfusion efficacy in severe CM-AIHA remains to be determined.