Patients with SCD are among one of transfused populations more often alloimmunized to red blood cell (RBC) antigens. Although transfusion services establish protocols of serologic matching and genotypic matching to reduce alloimmunization, there is still no consensus to the best practical approach although the obvious goal is to provide blood that will survive maximally. There are no studies comparing prophylactic genotypic matching to serologic matching. Based on this, our aim was to evaluate the effect prophylactic genotypic matching and serologic matching have on alloimmunization and hemolytic transfusion reactions in patients with SCD receiving regular transfusions. A prospective study was conducted in 29 patients with SCD undergoing red cell transfusions in a period of 5 years. Fifteen patients were receiving prophylactic extended (ABO, Rh, K, Fy a /Fy b , S/s) serologic matching and 14 patients were transfused with RBC units genotypic matched for Rh, K, Fy a /Fy b , S/s, Di a , Do a /Do b including Rh variants when possible. Serologic typing was performed by gel test (Biorad) and genotyping was performed by HEA, RHD and RHCE BeadChips (Immucor). The patients received a range of 15-407 RBC units and the median age was 36. Of the 15 patients receiving prophylactic serologic matching, 6 developed alloantibodies (1 anti-D, 2 anti-e, 1 anti-S, 1 anti-Fy a , -Do a and 1 anti-C, -Di a ). Three of those patients were not having a good in vivo RBC survival at the time of antibody detection as assessed by a decrease in their hemoglobin levels and an increase in the frequency of transfusions. Molecular analyses showed that the 4 patients who developed Rh antibodies had RH variant alleles predicting partial antigens and the patients who developed anti-S and anti-Fy a had discrepancies between the previous phenotype and genotype-derived phenotype. Of the 14 patients transfused with prophylactic genotypic matching RBC units, 2 were alloimmunized to Rh antigens (1 anti-D, 1 anti-e). Unexpected Rh antibodies found in these patients were not linked to expression of partial Rh phenotypes according to serological and molecular analyses but a result of altered Rh epitopes on transfused red cells. Our results showed that prophylactic genotypic matching is superior to phenotypic matching in patients with SCD especially if RH molecular matching is included, with the potential to decrease risk of transfusion reactions and to prevent alloimmunization.