The acute chest syndrome is a leading cause of death in patients with sickle cell disease, often precipitated by fat embolism and infection. A 30-center study analyzed 671 episodes of the syndrome in 538 patients to determine its causes, outcomes, and treatment responses. Nearly half of the patients were initially admitted for reasons other than the syndrome, and hypoxia, decreasing hemoglobin levels, and progressive multilobar pneumonia were common symptoms. The mean hospital stay was 10.5 days, with 13% requiring mechanical ventilation and 3% dying. Older patients and those with neurological symptoms were more likely to develop respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, and bronchodilators helped 20% of patients. Eighty-one percent of mechanically ventilated patients recovered. Infection was a contributing factor in 56% of deaths. The most common causes of death were pulmonary embolism and infectious bronchopneumonia. The study identified pulmonary fat embolism and 27 infectious pathogens as specific causes in 38% of episodes. Transfusions, bronchodilators, and antibiotics were effective treatments, and aggressive ventilatory support was successful in most cases.The acute chest syndrome is a leading cause of death in patients with sickle cell disease, often precipitated by fat embolism and infection. A 30-center study analyzed 671 episodes of the syndrome in 538 patients to determine its causes, outcomes, and treatment responses. Nearly half of the patients were initially admitted for reasons other than the syndrome, and hypoxia, decreasing hemoglobin levels, and progressive multilobar pneumonia were common symptoms. The mean hospital stay was 10.5 days, with 13% requiring mechanical ventilation and 3% dying. Older patients and those with neurological symptoms were more likely to develop respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, and bronchodilators helped 20% of patients. Eighty-one percent of mechanically ventilated patients recovered. Infection was a contributing factor in 56% of deaths. The most common causes of death were pulmonary embolism and infectious bronchopneumonia. The study identified pulmonary fat embolism and 27 infectious pathogens as specific causes in 38% of episodes. Transfusions, bronchodilators, and antibiotics were effective treatments, and aggressive ventilatory support was successful in most cases.