Background: Red blood cell (RBC) alloimmunization is an important transfusion complication, which is associated with post-transfusion hemolytic transfusion reactions. Sickle cell disease (SCD) individuals are particularly prone to the development of RBC antibodies following transfusions due to a number of factors, including the enhanced inflammation background caused by chronic hemolysis. Recent evidences show that dysregulation in molecules involved in innate immune response, such as toll like receptors (TLR), may underlie alloantibody development. Also, changes in immune-regulatory molecules, such as CTLA-4, have also been associated with alloimmunization. Goal: To investigate differences in the expression of genes encoding key molecules involved in innate immune response (TLR2, IL18 and CASP) and immune-regulatory molecules (HLA-G and CTLA-4) between alloimmunized and non-alloimmunized SCD individuals. Methods: Two groups of SCD participants were enrolled: 1) Alloimmunized : individuals presenting at least one IgG RBC alloantibody and 2) Non-alloimmunized : individuals with negative antibody screening after the transfusion of more than 10 RBC units. Real-time SYBR green quantitative PCR (qPCR) was performed to quantify the expression of TLR2, IL18, CASP, HLA-G and CTLA-4. ACTB was used as endogenous control. Mean Ct and delta Ct were determined for all included samples. Delta delta Ct and fold-change were calculated. Groups were compared in terms of mean Ct using the t-Student test. A p-value less than 0.05 was considered significant. Results: A total of 40 alloimmunized and 24 non-alloimmunized SCD participants were enrolled. The expression of CTLA-4 and TLR2 was significantly higher in the group of non-alloimmunized individuals in comparison to the alloimmunized participants: 1) CTLA4: fold-change of 0.23 (alloimmunized individuals) versus 0.57 (non-alloimmunized individuals) (p=0.0014) and 2) TLR2: fold-change of 1.5 (alloimmunized individuals) versus 9.96 (non-alloimmunized individuals) (p<0.0001). The expression of HLA-G , CASP and IL18 was not statistically different between the studied groups of individuals. Conclusion: In this case-control study, TLR2 and CTLA4 were differentially expressed between alloimmunized and non-alloimmunized SCD patients. This data sheds light to the role played by these two molecules on the RBC alloimmunization physiopathology.