One of the most important features of prolonged weightlessness is a progressive impairment of muscular function with a consequent decrease in exercise capacity. We tested the hypothesis that the impairment in musculo-skeletal function that occurs in microgravity results in a potentiation of the muscle metaboreflex mechanism and also affects baroreflex modulation of heart rate (HR) during exercise. Four astronauts participating in the 16 day Columbia shuttle mission (STS-107) were studied 72–71 days before launch and on days 12–13 in-flight. The protocol consisted of 6 min bicycle exercise at 50% of individual JOURNAL/jphy/04.02/00005245-200605010-00022/ENTITY_OV0312/v/2017-10-03T050437Z/r/image-pngO2,maxfollowed by 4 min of postexercise leg circulatory occlusion (PECO). At rest, systolic (S) and diastolic (D) blood pressure (BP), R-R interval and baroreflex sensitivity (BRS) did not differ significantly between pre- and in-flight measurements. Both pre- and in-flight, SBP increased and R-R interval and BRS decreased during exercise, whereas DBP did not change. During PECO preflight, SBP and DBP were higher than at rest, whereas R-R interval and BRS recovered to resting levels. During PECO in-flight, SBP and DBP were significantly higher whereas R-R interval and BRS remained significantly lower than at rest. The part of the SBP response (Δ) that was maintained by PECO was significantly greater during spaceflight than before (34.5 ± 8.8 versus 13.8 ± 11.9 mmHg, P= 0.03). The tachycardic response to PECO was also significantly greater during spaceflight than preflight (−141.5 ± 25.2 versus−90.5 ± 33.3 ms, P= 0.02). This study suggests that the muscle metaboreflex is enhanced during dynamic exercise in space and that the potentiation of the muscle metaboreflex affects the vagally mediated arterial baroreflex contribution to HR control.