 The FDA approval of macitentan for treatment of PAH represents a unique opportunity for study of the use of this medication in SCD. Endothelin-1 has long been established as an important mediator of vasoconstriction in SCD 19, 20 and more recent studies have implicated a role for this molecule in mouse models of PH in SCD 21. PH and an elevated TRV are both independent risk factors for mortality in SCD 1, 2, 9, 22 and, as the median age of death of SCD patients is in the 5th decade irrespective of a PH diagnosis, the possibility of therapeutically altering this outcome is of key importance in this disease. With the publication of the American Thoracic Society sponsored clinical guidelines for the diagnosis and treatment of PH in SCD additionally endorsed by the Pulmonary Hypertension Association and the American College of Chest Physicians, the timing for re-addressing the possibility of a clinical trial of a PAH therapy in this population perfect. We propose to utilize the information gathered from the trials which proceeded it to specifically design a clinical trial using macitentan to treat the SCD patients most likely to respond to this therapy; those with PAH-like hemodynamics without co-existent left-sided heart disease. 