Hemoglobin (Hb) S and Hb E are the most common variant hemoglobins, but because of the geographical separation of the areas where they are prevalent, the combination of the 2 is uncommon. Approximately 46 cases of hemoglobin SE compound heterozygosity have been reported. No deaths from the condition have been reported previously, whereas death after vigorous physical activity in individuals with sickle cell trait (hemoglobin AS) has been described in a few case reports. Here we report previously undiagnosed hemoglobinopathy SE in a 12-year-old American boy who collapsed during football practice and had a cardiac arrest on the field after a brief lucid interval. The autopsy was significant only for postmortem intravascular sickling. A postmortem hemoglobin electrophoresis test revealed 57% S, 34% E, and 1% F hemoglobins. The death is attributed to cardiac ischemia from functional vaso-occlusion by sickled erythrocytes.