Rationale: Sildenafil, a phosphodiesterase-5 inhibitor, could be useful for treating pulmonary hypertension (PH) in COPD. However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition. The study was designed to assess the acute hemodynamic and gas exchange effects of sildenafil in patients with COPD-associated PH. Methods: We conducted a randomized, dose comparison trial in 20 patients with COPD-associated PH. Eleven patients were assigned to 20mg and 9 to 40mg sildenafil. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion (V_A/Q) relationships, were assessed at rest and during constant-work rate exercise, before and 1 hour after sildenafil. Results: Both sildenafil doses reduced the mean pulmonary artery pressure (PAP) at rest and during exercise, without differences between them. Overall, PAP decreased -6 mmHg (95% confidence interval, -7 to -4) at rest and -11 mmHg (95%CI, -14 to -8) during exercise. After sildenafil, PaO₂ decreased -6 mmHg (95%CI, -8 to -4) at rest due to increased perfusion in units with low V_A/Q ratio, without differences between doses. No change in PaO2 (95%CI, -3 to 0.2 mmHg) or V_A/Q relationships occurred during exercise after sildenafil. Changes induced by sildenafil in PaO₂ and V_A/Q distributions at rest correlated with their respective values at baseline. Conclusion: In patients with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest and during exercise. This effect is accompanied by the inhibition of hypoxic vasoconstriction, which impairs arterial oxygenation at rest. The use of sildenafil in COPD should be done cautiously and under close monitoring of blood gases.