Background: Hypereosinophilic syndrome is characterized by peripheral blood eosinophilia and multiple organ system involvement. Only one case in a newborn has been reported. Case: Fetal sonography performed on a 33-year-old woman at 35 weeks’ gestation showed pericardial effusion and cardiomegaly. The infant was delivered by cesarean at 35 weeks’ gestation because of a worsening of the pericardial effusion. Hematologic studies revealed unexplained hypereosinophilia, and the pericardial fluid contained a large number of eosinophils. Chromosomal analysis revealed trisomy 21. The hypereosinophilia, pericardial effusion, and cardiomegaly all resolved after 8 weeks of steroid therapy. Conclusion: Hypereosinophilic syndrome caused pericardial effusion and cardiomegaly in a fetus with trisomy 21.