Background: Whether pulmonary hypertension at high altitude limits exercise capacity remains uncertain. We investigated if the reduction in hypoxic pulmonary vasoconstrictive response with corticosteroids or phosphodiesterase-5 inhibition improves exercise capacity to gain further insight into the pathophysiology of hypoxia induced pulmonary hypertension and the resulting reduction in exercise capacity. Methods and results: A cardiopulmonary exercise test and echocardiography to estimate systolic pulmonary artery pressure were performed in 23 subjects with previous history of high altitude pulmonary edema, known to be associated with enhanced hypoxic vasoconstriction. Subjects were randomized to dexamethasone 8mg bid, tadalafil 10mg bid, or placebo (double-blinded), starting the day before ascent. Measurements were performed at low and high (i.e. 4559m) altitude. Altitude exposure decreased maximum oxygen uptake and oxygen saturation, increased pulmonary artery pressure (pTR) and altered oxygen uptake kinetics. Compared to placebo, dexamethasone improved maximum oxygen uptake (% predicted: 74±13%, tadalafil 63±13%, placebo 61±11%, p<0.05), oxygen kinetics (mean response time 41±13s tadalafil 46±6s, placebo 45±10s, p<0.05), and reduced the ventilatory equivalent for CO₂ (42±4, tadalafil 49±4, placebo 50±5, p<0.01). Peak oxygen saturation did not differ significantly between the three groups (dexamethasone 66±7%, placebo 62±7%, tadalafil 69±5%, p=0.08). During echocardiography at low-intensity exercise (40% of peak power), dexamethasone compared to placebo resulted in lower pulmonary artery pressure (pTR) (47±9mmHg, tadalafil 57±11mmHg, placebo 68±23mmHg, p=0.05) and higher oxygen saturation (74±7%, tadalafil 67±3%, placebo 61±20, p<0.02). Conclusion. Corticosteroids, but not phodphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude.