1 Etablissement Français du Sang, Ile de France, Hôpital Henri Mondor, Créteil; 2 Centre de Référence des Cytopénies Auto-Immunes, Hôpital Henri Mondor, Créteil; 3 Service des Maladies Génétiques du Globule Rouge, Hôpital Henri Mondor Créteil; 4 Service de Médecine Interne, Hôpital Henri Mondor, Créteil; 5 Laboratoire d’Immunologie, Hôpital Henri Mondor, Créteil; 6 Université de Poitiers, EA 3806, CHU de Poitiers Correspondence: France Noizat-Pirenne, MD, PhD, Etablissement Français du Sang d’Ile de France, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. Tel: 331 56 72 76 37; Fax: 331 56 72 76 01, E-mail: france.noizat-pirenne{at}efs.sante.fr Delayed hemolytic transfusion reaction (DHTR), a life-threatening transfusion complication in sickle cell disease (SCD), is characterized by a marked hemoglobin drop with destruction of both transfused and autologous red blood cells (RBCs) and exacerbation of SCD symptoms. One mechanism of RBCs destruction is auto-antibody production secondary to transfusion. As rituximab specifically targets circulating B cells, we thought that it could be beneficial in preventing this immune-mediated transfusion complication. We report the case of a SCD patient who previously experienced DHTR with auto-antibodies and who needed a new transfusion. DHTR recurrence was successfully prevented by rituximab administration prior transfusion, supporting the safe use of rituximab to prevent DHTR in SCD patients as a second line approach when other measures failed. Key words: Sickle cell disease, rituximab, transfusion, auto-antibodies.