To determine the influence of a 17-d exposure to real and simulated spaceflight (SF) on cardiorespiratory function during exercise, four male crewmembers of the STS-78 Space Shuttle flight and eight male volunteers were studied before, during, and after the 17-d mission and 17 d of -6° head down tilt bedrest (BR), respectively. Measurements of oxygen uptake, pulmonary ventilation, and heart rate were made during submaximal cycling 60, 30 and 15 days before the SF lift-off (L-60, L-30, & L-15) and 12 and 7 days before BR (BR-12 & BR-7), on SF days 2, 8, and 13 (SF+2, SF+8, & SF+13) and on BR days 2 (BR+2), 8 (BR+8), and 13 (BR+13), and on days 1, 4, 5 and 8 (R+1, R+4, R+5 & R+8) after return to Earth and on days 3 and 7 after BR (R+3 & R+7). During L-15, R+4, and R+8 and all BR testing, each subject completed a continuous exercise test to volitional exhaustion on a semi-recumbent (SF) or supine (BR) cycle ergometer to determine the submaximal and maximal cardiorespiratory responses to exercise. The remaining days of the SF testing were limited to a workload corresponding to 85% of the peak pre-SF VO_2peak workload (VO_2-85W). Exposure to and recovery from SF and BR induced similar responses to submaximal exercise at 150 W. VO_2peak decreased by 10.4% from pre-SF (L-15) to R+4 and 6.6% from pre-bedrest to R+3, which was partially (SF: -5.2%) or fully (BR) restored within one week of recovery. VO_2-85W showed a rapid and continued decline throughout the flight (SF+2, -6.2%; SF+8, -9.0%), reaching a nadir of -11.3% during testing on SF+13. During BR VO_2peak also showed a decline from pre-BR (BR+2, -7.3%; BR+8, -7.1%; BR+13, -9.0%). These results suggest that the onset of and recovery from real and simulated microgravity induced cardiorespiratory deconditioning is relatively rapid and head down tilt bedrest appears to be an appropriate model of this effect both during and after spaceflight.