Acute regulation of blood pressure in humans is mediated by arterial baroreflex regulation of heart rate, cardiac contractility, and peripheral sympathetic outflow. Brief pharmacologic reductions of blood pressure were employed in 11 healthy volunteers to determine the effects of N2O on baroreflex-mediated increases in heart rate and efferent muscle sympathetic nerve activity. R-R intervals (ECG), blood pressure (radial artery), central venous pressure, respiratory rate (abdominal bellows), and end-tidal gas concentrations (mass spectrometer) were monitored. Efferent sympathetic nerve activity directed to skeletal muscle blood vessels (MSNA) was recorded from an epoxy-coated tungsten needle placed into the peroneal nerve. Data were obtained from six subjects before and during iv bolus administration of sodium nitroprusside (100 μg), during control while breathing 40% N2/60% O2, during administration of N2O (40% N2O/60% O2), and during recovery (40% N2/60% O2). Five subjects served as time controls and breathed 40% N2in O2throughout the protocol. Nitrous oxide produced a 59 ± 18% (P< 0.05) increase in baseline MSNA but did not alter the reflex augmentations in MSNA produced by nitroprusside. In contrast, there was a 39 ± 14% decrease in the slope of the relationship between systolic pressure and R-R interval (P< 0.05) in subjects breathing N2O. N2O thus produces activation of the sympathetic nerves directed to skeletal muscle blood vessels, and it decreases baroreflex-mediated tachycardia without diminishing baroreflex-mediated augmentations in sympathetic outflow.