Neonatal hemochromatosis is an uncommon disorder, clinicopathologically defined by severe and generally fatal liver disease of intrauterine onset associated with extrahepatic siderosis that spares reticuloendothelial elements (hemochromatotic siderosis). The agent or agents of liver disease in neonatal hemochromatosis are not known. It also is not known if intrauterine liver disease of defined infective etiology can lead to hemochromatotic siderosis. We present two patients with fetal liver disease and hemochromatotic siderosis whose cases help address these points. In the first patient rare hepatobiliary and numerous renal tubular cytomegalovirus (CMV) inclusions were found; CMV infection was confirmed by the polymerase chain reaction. Studies of the mother of the second patient 1, 5, and 9 weeks post-partum showed recent seroconversion against CMV; seroconversion against other infectious agents (toxoplasma, rubella, herpes, parvovirus B19, hepatitis A/B/C) was not present. Histologic, immunohistochemical, in situ hybridization, or polymerase chain reaction evidence of CMV infection was not present in infant tissues, even though peripartum maternal seroconversion against CMV was observed. We conclude that hemochromatotic siderosis may accompany chronic fetal liver disease of defined infective etiology (patient no. 1) and that recent maternal seroconversion against CMV in the presence of severe fetal liver disease does not necessarily mean that transplacentally acquired CMV infection caused the fetal liver disease (patient no. 2). Polymerase chain reaction documentation of infective-agent genomic sequences in fetal or infant tissues permits more accurate interpretation of maternal serologic data.