We present an unusual case, in which a woman presenting with markedly decreased fetal movements at 29 weeks gestation following a recent increase in fundal height was noted sonographically to have fetal hydrops consisting of scalp edema, marked hepatomegaly, ascites, and polyhydramnios. No lethal structural congenital anomaly was noted. Admission laboratory examinations revealed a negative antibody screen and a negative RPR. Emergent cesarean section was performed due to prolonged fetal bradycardia during biophysical profile testing. The acidotic hydropic neonate weighing 1825 g was resuscitated yet succumbed at 3 hr of life following intravenous administration of antibiotics. Neonatal blood was RPR positive at 1:16. Postmortem pathology examination demonstrated severe multiorgan system failure secondary to overwhelming congenital syphilis. Extensive extramedullary hematopoiesis was noted and histopathology with Dieterle stains revealed numerous hepatic spirochetes. Postpartum reexamination of the maternal blood with serial dilutions revealed a positive RPR at 1:1024. This case emphasizes that initial negative screening for syphilis may be seen despite overwhelming infection, a condition that has been termed the "prozone effect."