The paper describes the cases of three siblings affected by Hereditary Spherocytosis (HS). The different clinical presentations in the same family are examples of the heterogeneity of this pathology. HS is a common inherited type of haemolytic anaemia that results from abnormal morphology of erythrocytes. The clinical spectrum of HS ranges from asymptomatic forms characterized by well-compensated chronic haemolysis to severe forms with high transfusion requirement. The typical symptoms triad is anaemia, jaundice and splenomegaly while the most common complication is cholelithiasis. The diagnosis of hereditary spherocytosis in the neonate can be difficult, due to different clinical and laboratory presentations. Neonatal HS ratio, calculated by dividing the MCHC by the MCV, is a rapid and inexpensive screening. Splenectomy helps improve the patient’s quality of life and may be performed after six years of age. RHuEPO therapy should be considered in affected infants with high transfusion requirement.