Background: Rh antibodies in patients with sickle cell disease (SCD) is associated with the lack of the corresponding conventional antigens on red blood cells (RBCs) or may be a result of inheritance of altered RH alleles or a result of altered epitopes on donor RBCs. However, the clinical significance of these Rh antibodies may have varying clinical effect. The aim of this study was to evaluate the clinical significance of the Rh antibodies in SCD patients with unexpected Rh antibodies receiving serologic Rh-matched RBC units. Methods: We selected 15 patients with Rh antibodies (11 patients with variant RHCE alleles and 4 patients with the corresponding conventional RH alleles receiving serologic Rh-matched RBC units). All patients were phenotyped for D, C, c, E, e by hemagglutination in gel cards and genotyped with RHD and RHCE BeadChip arrays (Bioarray, Immucor). Sanger sequencing was performed when necessary. Antibody screening and identification with autologous control were performed by gel test. Direct antiglobulin test, adsorption with autologous RBCs and crossmatching with allogeneic partial RBC antigens when possible were also performed. The clinical significance of the antibody was assessed by comparison of the hemoglobin levels recorded before and after transfusion at the time of antibody detection and by clinical suspicion of anemia and hemolysis. Results: Serological features of the identified Rh antibodies were compatible with the presence of alloantibodies. Anti-C was identified in 4 patients with the hybrid allele RHD*DIIIa-CE (4–7)-D encoding partial C and in 1 patient with conventional C antigen. Anti-e was identified in 7 patients with variant RHCE alleles (2 RHCE*ceAR, 3 RHCE*ce733G and 2 RHCE*ceS) and in 3 patients with the corresponding e antigen. The 5 patients with anti-C and the 2 patients with anti-e who were genotyped as RHCE*ceAR homozygous presented laboratory evidence and clinical symptoms of anemia and hemolysis compatible with a delayed hemolytic transfusion reaction (DHTR) at time of antibody detection. The other 8 patients had a good survival of the transfused RBCs. Conclusions: All anti-C antibodies (produced by patients with partial C or probably derived by variant Rh on donor RBCs) showed clinical significance but only the anti-e produced by patients with RHCE*ceAR variant allele was related to DHTR. The clinical significance of Rh antibodies produced by SCD patients with RH variant alleles or due to altered epitopes on donors RBCs may vary according to the specific variant inherited or exposed.