Pulmonary hypertension is associated with sudden death and is a risk factor for mortality in adult patients with sickle cell disease. The high mortality despite only mild-to-moderate increases in pulmonary vascular resistance remains an unresolved paradox. Accordingly, little is known about the cardiovascular effects of stressors, such as vaso-occlusive pain crisis (VOC) and exercise, which may acutely increase pulmonary pressures and impair right heart function. We therefore evaluated pulmonary artery pressures by echocardiogram in 25 patients with sickle cell disease in steady-state and during VOC, and by right heart catheterisation with exercise in a second cohort of 21 patients to determine whether pulmonary hypertension worsens during acute cardiopulmonary stress. TRV increased during VOC (P < 0.001), and the increased pulmonary pressures during VOC were associated with decreases in haemoglobin levels (P < 0.001), and increases in lactate dehydrogenase (P < 0.001) and plasma haemoglobin levels (P = 0.03). During exercise stress performed during cardiac catheterisation, mean pulmonary artery pressures (P < 0.001) and pulmonary vascular resistance increased (P < 0.001) in all subjects. These data suggest that acute elevations in pulmonary pressures during VOC or exercise may contribute to morbidity and mortality in patients with sickle cell disease.