Jaundice is a less frequent sign in infectious mononucleosis, more often caused by hemolysis, rarely by hepatocytes damage. In subjects with erythrocyte plasmatic membrane defects such as spherocytosis, any infection could increase hemolysis. The authors describe the case of a young spherocytosis patient in whom Epstein-Barr virus caused an intense cholestatic jaundice and they discuss the possible damage mechanisms according to the recent studies on cholestasis pathogenesis.