PURPOSE: To document the cardiopulmonary responses to submaximal exercise during long-duration International Space Station (ISS) missions. METHODS: Astronauts (n=14) assigned to ISS missions (range: 91-192 d) performed cycle exercise testing ~90 d before launch, ~15 d after launch and every ~30 d thereafter. Peak oxygen consumption (VO2pk) data were previously reported (Moore, et al, 2014). Heart rate (HR, ECG), and oxygen consumption (VO2, Portable Pulmonary Function System, DAC, Denmark) were measured at rest and during 5-min work rates prescribed to elicit 25, 50, and 75% of preflight VO2pk. Cardiac output (Q, Freon 22/SF6 technique) was measured at rest and the 25 and 50% stages. Stroke volume (SV) and arterial-venous oxygen difference (a-v O2d) were calculated. Inflight outcomes were compared to preflight values using mixed-model linear regression with preflight body weight as a covariate. To account for multiplicity, significance thresholds for P values were adjusted (Hochberg procedure). No time trend during flight was evident, thus inflight data are reported as a single outcome. RESULTS: During spaceflight, neither resting VO2 (Pre: 0.41 ± 0.12, In: 0.33 ± 0.07 L/min; Mean ± SD) nor HR (Pre: 71 ± 10, In: 69 ± 11 bpm) differed from preflight, but resting Q (Pre: 5.8 ± 0.9; In: 7.6 ± 0.9 L/min) and SV (Pre: 83 ± 19, In: 112 ± 21 ml/beat) were higher while resting a-v O2d was lower (Pre: 7.0 ± 2.0, In: 4.4 ± 0.8 ml O2/100 mL). During exercise, VO2 was lower at the 25% stage during flight (Pre: 0.95 ± 0.19, In: 0.81 ± 0.14 L/min), but did not differ from preflight during any other exercise stage. Inflight HR did not differ from preflight in the 25% stage (Pre: 88 ± 11, In: 89 ± 14 bpm), but HR was elevated during the 50% stage (Pre: 113 ± 15, In: 122 ± 16 bpm) and the 75% stage (Pre: 147 ± 16, In: 158 ± 16 bpm). In contrast to rest, exercise Q and SV did not differ from pre- to inflight, although a-v O2d was reduced during both the 25% stage (Pre: 9.8 ± 0.8, In: 7.7 ± 0.5 ml O2/100 mL) and the 50% stage (Pre: 12.8 ± 0.9, In: 10.2 ± 0.8 ml O2/100 mL). CONCLUSION: Lower VO2 during the 25% stage on ISS may result from reduced metabolic cost of pedal upstroke. Maintained exercise Q and SV during flight suggest central cardiovascular factors did not limit submaximal exercise at these levels. Lower a-v O2d during flight may be related to altered blood flow distribution in space.