Introduction: Autoimmune hemolytic anemia (AIHA) is a rare and diverse group of acquired hemolytic anemias which results from increased destruction of red blood cells (RBCs) due to autoantibodies directed against antigens on the RBC surface. Currently, there are no clearly defined evidence-based guidelines on the management of AIHA, and current treatment options are based on small retrospective studies, case reports, as well as expert experiences and recommendations. We report a case of severe idiopathic mixed AIHA that responded to a combination of steroids, intravenous immunoglobulin (IVIG) and bortezomib. Case Report: A 25-year-old African American female presented with jaundice, shortness of breath, and abdominal pain. She had splenomegaly on examination and initial work-up was significant for severe anemia (hemoglobin, 3.3 g/dl) and hyperbilirubinemia (total bilirubin, 26.7 mg/dl; direct bilirubin, 21.9 mg/dl). Direct antiglobulin test (DAT) was microscopically positive for anti-IgG and anti-C3d, and cold autoantibodies were identified. An extensive workup for a possible secondary cause of her anemia was non-revealing. She was sequentially treated with prednisone, IVIG, and bortezomib. Marked response was noted as evidenced by improvement in the hemoglobin from a nadir of 3.2 g/dl on admission to 10.1 at discharge. Patient has remained clinically in remission since then. Conclusion: The first line treatment for warm AIHA (w-AIHA) includes glucocorticoids and transfusion of least incompatible RBCs. Steroids are rarely necessary or effective in cold agglutinin AIHA in which case high dose IVIG and plasmapheresis have been used albeit with inconsistent results. Bortezomib is an inhibitor of the 26S proteasome and is approved for the treatment of multiple myeloma. It has been reported to have some activity in rituximabresistant cold agglutinin disease (CAD) due to its activity against the CD20-negative plasma cell compartment that may be responsible for IgG anti-RBC autoantibody production.