Rhesus (Rh) isoimmunization presenting as severe neonatal hemolytic disease is rare in RhD negative primigravidas of Chinese ethnicity. We report the case of a 32-year-old pregnant Taiwanese woman, RhD negative, who gave birth vaginally to two RhD-positive full-term fetuses 6 years apart. Antenatal follow-up was uneventful and there was no obvious fetal-maternal hemorrhage except at the performance of amniocentesis at the 19th week of the first pregnancy without anti-D immune globulin prophylaxis. Although anti-D immune globulins were administered to the mother within 1 hour after each birth, both of the newborns had severe neonatal hemolysis refractory to phototherapy and were rescued by exchange transfusions. Both of the children were well at age 7-years-old and one-year-old respectively In conclusion, with suspicion of fetal-maternal hemorrhage in RhD-negative pregnancies post amniocentesis, serial monitoring of indirect Coombs titer with appropriate management is mandatory.