Both acute hypoxia and sildenafil may influence autonomic control through transient cardiovascular effects. In a double-blind study, we investigated whether sildenalfil could interfere with cardiovascular effects of hypoxia. Twelve healthy men (placebo, PLA n = 6; sildenalfil, SIL n = 6) were exposed to 4,350m during six days. Treatment was continuously administered from 6-8 hours after arrival at altitude (3x40mg/day). The autonomic control on the heart was assessed by heart rate variability (HRV) during sleep at sea level (SL), between days 1-2 (D1-2) and days 5-6 (D5-6) in hypoxia. Arterial pressure (AP) and total peripheral resistances (TPR) were obtained during daytime. There were no statistical difference between groups in HRV, AP, and TPR throughout the study. Hypoxia induced a decrease in R-R interval and an increase in AP in both groups. Low frequency/high frequency ratio increased at D1-2 (PLA, P = 0.04; SIL, P = 0.02) and D5-6 (PLA and SIL, P = 0.04) versus SL, while normalized high frequency power decreased only in PLA (P = 0.04, D1-2 vs SL). Normalized low frequency power increased at high altitude (PLA and SIL, P = 0.04, D5-6 vs SL). TPR decreased at D2 in PLA (P = 0.02) and tended to normalize at D6 (P = 0.07, D6 vs D2). Acute hypoxia induced a decrease in parasympathetic and increase in sympathetic tone which tended to be reversed with acclimatization. Sildenafil had no deleterious effects on the cardiovascular response to high altitude exposure and its control by the autonomic nervous system.