Anemia, mental status changes, and fatal respiratory failure complicated a febrile illness in a previously healthy 14-year-old black female. At autopsy, widespread fat emboli and bone marrow necrosis were found. Hemoglobin electrophoresis on an antemortem, pretransfusion specimen revealed hemoglobin S/beta+ thalassemia. Acute parvovirus B19 (PV B19) infection was suspected. Postmortem serum and a variety of paraffin-embedded tissues were assayed for PV B19 DNA using the polymerase chain reaction (PCR). The expected PCR product was identified in the serum specimen and in paraffin-embedded sections of bone marrow, kidney, spleen, parathyroid, thyroid, adrenal, and gastrointestinal tract: lung, liver, ovary, fallopian tube, uterus, brain, heart, and pancreas were negative. PV B19 infection is highly contagious and may be rapidly fatal in children with hemoglobinopathies by several mechanisms, including fat embolism. Therefore, there exists the risk of multiple deaths within a family. The acute infection may be easily and expeditiously diagnosed using serum or a variety of paraffin-embedded tissues.