Sickle cell disease (SCD) manifests itself with vaso-occlusive episodes leading to infarction. Placement of intravascular catheters provides a useful route for management of pain crises as well as other complications. However, catheter misuse is a commonly unrecognized problem, which can have lethal consequences. We present a case of fatal splenic sequestration/hyperhemolysis secondary to foreign body pulmonary and systemic embolization due to intravenous administration of hydromorphone pills in a young woman with SCD. Morphological identification of the embolized particles (crospovidone, microcrystalline cellulose, and hydrophilic polymer) was key in understanding the mechanism of death. Foreign particle deposition induced a granulomatous inflammatory response that resulted in obliteration and distortion of the microvasculature, thus triggering sickling with subsequent organ damage. Despite clinical evidence of asplenia and microscopic white pulp fibrosis with Gamna-Gandy body formation, unexpectedly for the patient's age, the spleen was enlarged by entrapped sickle cells. The findings support the possibility that loss of function can coexist with increased splenic activity under certain circumstances, an overlooked clinical phenotype of SCD. This case illustrates the teaching value of classic autopsy in addition to its crucial role in understanding the natural history of complex heterogeneous diseases.