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Transfusion therapy is a life‐sustaining treatment for patients with sickle cell disease (SCD), but can cause serious complications including alloimmunization. We previously reported diminished regulatory T cells (Tregs) and skewed Th2 responses in alloimmunized SCD patients. We hypothesized that the B cell regulatory (Breg) compartment, which controls Treg and Th differentiation, may also be compromised in allosensitized SCD patients. Phenotypically, we did not find differences in the frequency or numbers of CD24^hiCD38^hi and CD24^hiCD27⁺ B cell subsets, both previously identified as human Bregs, between alloimmunized and non‐alloimmunized SCD patients on regular transfusions. However, at the functional level, CD19+ B cells from alloimmunized SCD patients expressed lower levels of IL‐10 following stimulation as compared with non‐alloimmunized patients (P < 0.05), and had reduced ability in …