The blood bank received a hemolyzed specimen (see left figure, left tube, preplasmapheresis specimen) from a 56-year-old male with marked anemia (Hb, 5.1 g/dL), fatigue, tachycardia, and a strong cold antibody reactive with all panel cells. He was treated for cold agglutinin disease with steroids, IVIG, rituximab, cyclophosphamide, and transfusion through a blood warmer with mild improvement. Unfortunately, the patient remained transfusion dependent with a decreasing but still elevated LDH. An extensive investigation to rule out malignancy was performed but revealed only lymphadenopathy, mild splenomegaly, and erythroid hyperplasia on marrow biopsy. The cold antibody was nonreactive with enzyme-treated RBCs and was identified as anti-Pr. The DAT was weakly positive (RBC-bound C3). The antibody was reactive at 30°C and very weakly reactive at 37°C. The antibody was predominantly IgM, but microscopic reactivity remained in DTT-treated serum, suggesting a minor component of IgG. The titer was abnormal but not extremely high (128 at 4°C). Pr is present on almost all human RBCs and carried on oligosaccharide side chains attached to RBC membrane-borne glycophorins 1 (majority on glycophorin A). A new explanation for the pathophysiology of hemolysis caused by this antibody in a context of unimpressive serologic results was described by Brain and colleagues 2 and Garratty 3 and involves antibody-induced aggregation of glycophorin A causing destabilization of the RBC membrane phospholipid bilayer, leading to an increase in cation permeability. The patient's room was kept as close to 37°C as possible. To hasten recovery and transition to outpatient treatment, plasmapheresis was initiated to further facilitate removal of the cold antibody. The cold agglutinin disease was treated and hemolysis stabilized by the use of a multimodal approach to therapy, including immunosuppressant medications, IVIG, RBC transfusion, and plasmapheresis: acute hemolysis resolved (see left figure, right tube, postplasmapheresis specimen) and the decrease in LDH accelerated (see figure, right, hospital time course). After two plasmapheresis procedures the patient was discharged with a Hb of 6.9 g/dL but continued to receive weekly outpatient transfusions. This case illustrates the lack of correlation between the relatively benign serology related to anti-Pr and the severity of hemolytic anemia. Plasmapheresis can play an important role in the multimodal treatment of cold agglutinin disease and the transition to outpatient treatment.