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Red blood cell exchange (RBCE) is the standard of care for patients with sickle cell disease (SCD) who present with severe vaso-occlusive crisis (VOC). However, subsets of these critically ill patients have progressive multiorgan failure (MOF) despite RBCE therapy. The purpose of this case series is to describe the use of plasma exchange (PLEX) for the treatment of SCD-related MOF that is refractory to RBCE.A retrospective case review of patients with severe MOF from sickle cell crisis unresponsive to RBCE who underwent PLEX in a 14-bed adult medical intensive care unit (ICU) at a tertiary care university hospital over a 4-year time period. Key laboratory data including complete blood count, indices of hemolysis, and markers of organ failure were recorded before and after both RBCE and PLEX.Our primary objective is to evaluate the effectiveness of PLEX, in addition to RBCE, on organ dysfunction, laboratory indices, and mortality. Of the 7 patients, 6 survived. Of the patients who survived, all remained hemodynamically stable during PLEX sessions and showed both clinical and laboratory evidences of improvement in hemolysis and organ function. Average time from completion of first PLEX treatment to initial laboratory signs of organ failure reversal for patients who survived was 15.6 hours, the average length of stay in the ICU was 5.6 days, and the average total length of stay in the hospital was 14 days.Plasma exchange, in addition to RBCE, may be a novel synergistic treatment option to decrease risk of mortality in patients with refractory VOC and MOF.