Cardiac vagal withdrawal when moving from supine to an upright posture may be independent of respiratory sinus arrhythmia. Further, ventilatory efficiency of an upright lung may improve with clustering of heart beats during inhalation. We studied healthy human subjects (n=8, 6 male) during supine rest (SUP) and 80 degrees head-up tilt (HUT). ECG and expired breath were sampled continuously to determine heart rate, mean and end-tidal (ET) fractional content (F) of O2 and CO2, tidal volume (V(T)) and breathing frequency (Bf). HUT increased heart rate (47+/-3 vs. 59+/-9 beats min(-1), p<0.01), decreased the high frequency component of heart rate variability (8.76+/- vs. 7.07+/-1.12, p<0.05), and increased the ratio of low to high frequency components in the heart rate (0.62+/-0.6 vs. 1.79+/-2.07, p<0.05). HUT did not change VT, Bf, or minute ventilation (V'E), but decreased FCO2 (4.90+/-0.48 vs. 4.56+/-0.42 %, p<0.05) and FETCO2 (6.64+/-0.24 vs. 6.30+/-0.27 %, p<0.01). HUT increased the CO2 ventilatory equivalent (24.88+/-2.50 vs. 26.74+/-2.61, p<0.01). Mean heart rate during inhalation increased with HUT (26+/-3 vs. 34+/-6 beats min-1), with no change during exhalation. Increased clustering of heart beats during inhalation independent of a decrease in HF cardiac variability may partly offset decreases in ventilatory efficiency of an upright lung.