Pulmonary hypertension is a common co-morbidity of sickle cell disease with an associated increased mortality risk, but its etiology is not well-understood. To evaluate the hemodynamic characteristics, clinical predictors, and cardiovascular manifestations of elevated pulmonary arterial pressure in this population, we performed noninvasive hemodynamic assessments of 135 patients with sickle cell disease using Doppler echocardiography. A diagnosis of pulmonary hypertension was determined by gender-, age-, and body mass index-specific normal reference ranges for tricuspid regurgitation jet velocities (TRVs). A high TRV was noted in 34 patients (25%). Pulmonary vascular resistance was elevated in only 2 (6%) of the 34 patients with suspected pulmonary hypertension but was significantly greater than in those with normal TRV. On univariate regression, the TRV correlated with age, body mass index, left atrial pressure, and right ventricular stroke volume and was negatively associated with hemoglobin and glomerular filtration rate. The left atrial pressure, right ventricular stroke volume, and hemoglobin remained independent predictors of TRV in a multivariate model. A greater TRV was also associated with larger right ventricular and right atrial chamber sizes and greater N-terminal probrain natriuretic peptide levels. In conclusion, our results suggest that the mild elevation in TRV often observed in patients with sickle cell disease is rarely associated with a high pulmonary vascular resistance and that multiple factors—including the compensatory high output state associated with anemia, pulmonary venous hypertension, and pulmonary vasculopathy—can contribute to an elevated pulmonary arterial pressure in these patients.