Sudden death in the setting of sickle cell lung disease (SCLD), is periodically seen in the practice of medical examiners. The goal of the present study was to identify the most common pathologic findings of SCLD associated with sudden or unexpected death. A retrospective/prospective review of 21 autopsy cases from sickle cell patients between 1990 and 2004 was performed. Review of medical records, autopsy reports, and H&E-stained slides of lung tissue was performed. Oil-Red-O and elastic staining of lung tissue were evaluated. All cases were screened for both acute and chronic forms of SCLD. Patients admitted for sickle cell pain crisis ranged in age from 8 months to 65 years. Fifteen out of 21 cases (71.4%) showed significant pulmonary pathology. The most frequent lung findings included pulmonary edema (47.6%), pulmonary thromboembolism (38.1%), fat emboli (33.3%), pulmonary hypertension, grades I-IV (33.3%), and microvascular occlusive thrombi (28.5%). Our study demonstrates higher-than-expected percentages of acute and chronic sickle cell-related lung injury such as fat embolism (33.3%) and pulmonary hypertension (33.3%), with right ventricular hypertrophy (33.3%). Therefore, we propose a simple and high-yield autopsy algorithm of ancillary procedures that should be applied on all known and suspected autopsy cases of sickle cell disease.