Introduction: Hyperhemolysis is a life-threatening condition of exaggerated hemolysis of red blood cells which occurs in patients receiving chronic transfusion therapy. Results: We present a 19-year-old male with β-thalassemia major with an episode of hyperhemolysis. Hemolysis was initially unresponsive to immunosuppression, but responded to with the addition of eculizumab. Several weeks after stabilization, hemolysis returned which was also successfully managed with immunosuppression and eculizumab. Discussion: Hyperhemolysis is unique in β-thalassemia due to the underlying dysfunctional erythropoiesis and transfusion dependence. Immunosuppression with eculizumab successfully slowed the hemolysis and allowed for resumption of transfusions.