Objectives To compare the effect of semi-recumbent and sitting positions on gas exchange, respiratory mechanics and hemodynamics in patients weaning from mechanical ventilation. Background Upright positions are encouraged during rehabilitation of the critically ill but there effects have not been well described. Methods A prospective, randomized, cross-over trial was conducted. Subjects were passively mobilized from supine into a seated position (out of bed) and from supine to a semi-recumbent position (>45ࠢackrest elevation in bed). Arterial blood gas (PaO2/FiO2, PaO2, SaO2, PaCO2 and A-a gradient), respiratory mechanics (VE,VT, RR, Cdyn, RR/VT) and hemodynamic measurements (HR, MABP) were collected in supine and at 5 min and 30 min after re-positioning. Results Thirty-four intubated and ventilated subjects were enrolled. The angle of backrest inclination in sitting (67 ᠵ੠was greater than gained with semi-recumbent positioning (50 ᠵଠp < 0.001). There were no clinically important changes in arterial blood gas, respiratory mechanic or hemodynamic values due to either position. Conclusions Neither position resulted in significant changes in respiratory and hemodynamic parameters. Both positions can be applied safely in patients being weaned from ventilation.