BACKGROUND: Cold agglutinin disease (CAD) or syndrome (CAS) can be particularly challenging when autologous stem cell transplant (ASCT) is needed. Standard peripheral blood stem cell (PBSC) collection and manipulation involve ex vivo blood manipulations at lower than body temperature, predisposing to agglutination during graft collection, handling, processing, and infusion. STUDY DESIGN AND METHODS: We describe the first case of ASCT for relapsing lymphoma in a patient with high-titer CAD requiring anti-complement therapy and chronic transfusion. To prevent agglutination, five therapeutic plasma exchange sessions were performed prior to PBSC collection. Optimal thermal conditions were maintained using various approaches to increase the temperature of the room, venous return lines, and the apheresis device. Ex vivo graft manipulation was conducted under similar conditions. An infusion test was performed with a fraction of the graft a month prior to ASCT to confirm tolerability. RESULTS: The infusion test was performed without complications. A month later, the patient was admitted for ASCT. The aplasia phase was particularly challenging, as the patient experienced a rapid drop in hemoglobin levels due to hemolysis without compensatory reticulocytosis. Twelve months after ASCT, chronic hemolysis persists, but the patient is now transfusion-free, and the lymphoma remains in remission. DISCUSSION: Performing ASCT in patients with clinically significant CAS or CAD is challenging but can be done safely. Strong coordination between the apheresis team, cell therapy laboratory, and clinical unit is paramount to the success of this procedure. The experience gained from this case may also be applicable to other cell therapy procedures.