Cerebrovascular CO₂ reactivity is affected by nitric oxide (NO). We tested the hypothesis that sildenafil selectively potentiates NO-cGMP signaling affects CO₂ reactivity. Fourteen healthy males (34±2 years) were enrolled in the study. BP, ECG, velocity of cerebral blood flow (CBF, measured by TCD), end tidal CO₂ (EtCO₂) were assessed at baseline (CO₂ ~ 39 mm Hg), during hyperventilation (CO₂ ~ 24 mm Hg), hypercapnia (CO₂ ~ 46 mm Hg), boluses of phenylephrine (25-200 µg) and during graded head-up tilting (HUT). Measurements were repeated one hour after taking 100 mg sildenafil. Results showed that sildenafil did not affect resting BP, HR, CBF peak and mean velocities, eCVR (mean BP/mean CBF), breath/min, and EtCO₂: 117±2/67±3 mm Hg, 69±3 bpm, 84±5 and 57±4 cm/sec, 1.56±0.1 mmHg/cm*sec, 14±0.5 breaths/min and 39±0.9 mm Hg, respectively. Sildenafil increased and decreased the hypercapnia-induced in CBF and eCVR, respectively. Sildenafil also attenuated the decrease in peak velocity of CBF, 25±2% vs. 20±2% (p<0.05), and increased the eCVR, 2.5±0.2% vs. 2±0.2% (p<0.03) during hyperventilation. Sildenafil did not affect CBF despite significant increases in the eCVRs that were elicited by phenylephrine and HUT. This investigation suggests that sildenafil, which potentiates the NO-cGMP signaling, seems to affect the cerebrovascular CO₂ reactivity without affecting the static and dynamic pressure-dependent mechanisms of cerebrovascular autoregulation.