Next to A and B antigens, agglutinogen D exhibits the highest immunogenicity. Following the transfusion of D-positive red blood cells (RBCs), almost 80% of D-negative recipients develop anti-D antibodies (Abs). Subsequently, anti-D immunization further promotes the synthesis of Abs towards other blood group antigens in or outside the Rh system. The D antigen is also involved in 95% of cases of hemolytic disease of the newborn. Transfusions, hemotherapy, grafts, and obstetric history (abortions, ectopic pregnancy, births) are all risk factors for Rh isoimmunization. In the case of ABO compatibility between mother and fetus, Rh-positive fetal RBCs that have reached the maternal bloodstream are not destroyed by group agglutinins, and Rh antigenic sites are not hidden by the maternal immune system. But a Rh-negative mother with a homozygous Rh-positive husband will certainly have a Rh-positive fetus. As it has an irreversible evolution, the Rh isoimmunization once installed cannot be influenced in the sense of decreasing the Ab titer, therefore, injectable globulin has no effect. A particular case was that of a newborn with Rh system incompatibility associated with hereditary spherocytosis The clinical balance at birth reflects the severe jaundice of the female newborn of 3140 g, gestational age 38∕39 weeks, extracted by lower-segment transverse Caesarean section, with a double loop nuchal cord, Apgar score 8. Because the jaundice was severe and atypical (face and upper chest), we considered the possibility of coexistence of hemolytic disease of the newborn by Rh blood group incompatibility associated with hereditary spherocytosis, as it turned out to be true and mentioned. Changes in genes encoding proteins in the structure of the RBC membrane have amplified hemolysis induced by maternal-fetal isoimmunization in the Rh system. Massive hemolysis accentuated by congenital spherocytosis, confirmed later, imposed blood transfusion and dynamic monitoring.