Rationale: Steady-state mild pulmonary hypertension is a risk factor for death in adults with sickle cell disease. Acute pulmonary hypertension has been reported during exercise and vasoocclusive pain crisis in these patients. Objectives: The aim of the present study was to evaluate changes in pulmonary pressures and cardiac biomarkers during severe acute chest syndrome and their associations with mortality. Methods: We prospectively evaluated 70 consecutive adults who received standardized treatment in our intensive care unit for a total of 84 episodes. At admission, cardiac biomarkers were measured. Transthoracic echocardiography was performed for pulmonary hypertension assessment via measurement of tricuspid regurgitant jet velocity and was repeated when possible after resolution. Measurements and Results: Tricuspid jet velocity was <2.5 m/s in 34 (40%) of the 84 episodes, 2.5 to 2.9 m/s in 19 (23%), and 3 m/s in 31 (37%). Cor pulmonale occurred in 11 (13%) episodes. Tricuspid jet velocity showed significant positive correlations with Brain-Natriuretic Peptide (rho=0.54, P<0.01) and cTroponinI (rho=0.42, P<0.01). Pulmonary pressures increased compared to steady state then decreased after resolution. All five patients who required invasive ventilation and all four patients who died during the immediate hospital course had jet velocity values 3 m/s. Overall mortality was 12.9% (9 patients) and survival was significantly lower in patients whose jet velocity was 3 m/s during at least one episode, compared to the other patients (P<0.01). Conclusions: Pulmonary pressures increase during severe acute chest syndrome, and pulmonary hypertension is associated with cardiac biomarker elevation and a higher risk of death.