The subject had visited his local physician the day before his death, complaining of cold, cough, and fever. A physical examination revealed his temperature was 99 degrees F, and the oropharynx appeared reddened. Prescriptions were given for vitamins and cough suppressants. The next morning he complained of chest pain, and 10 hours later he was found dead in his home. The only past medical history was a diagnosis of sickle cell trait made when he was a child. There was no history of crises or other medical complaints due to this diagnosis. The postmortem examination revealed a well-developed, well-nourished, 262 lb, 70-inch male. Internal examination showed a 1,132 g spleen that measured 25x15x10 cm. The heart weighed 404 g, and the left ventricle was 1.5 cm in thickness. There was some myxomatous change of the mitral valve. Histologically, there was vascular dilation and congestion with abnormally shaped and sickled red blood cells in the spleen and other parenchynmal organs, including the heart and brain. Macrovesicular steatosis was present within the liver sections. Examination of a postmortem blood smear revealed many abnormal and sickled red cells. There was 29 percent hemoglobin A and 71 percent hemoglobin S on electrophoresis. Molecular diagnostics on genomic DNA isolated from peripheral blood white cells showed that the patient was doubly heterozygous for sickle cell and B-thalassemia genes; this led to an accurate diagnosis of sickle cell-B+ -thalassemia. Blood and splenic cultures revealed only postmortem growth. Vitreous electrolytes were not diagnostic of dehydration. Toxicologic analysis on blood revealed trace amounts of Amitriptyline and Nortriptyline. Unfortunately, the specific precipitating factors leading to death in this case are unknown. Because fatalities, although rare, have been described in association with these sickle cell syndromes, it is important that these disorders be considered in autopsy and other postmortem procedures designed to determine cause of death. 1 figure and 14 references