Landing day symptoms from orthostatic hypotension after prolonged spaceflight can be debilitating, but severity of these symptoms can be unpredictable and highly individual. We tested the hypothesis that an impaired baroreflex response to an inflight leg cuff test could predict orthostatic intolerance on return to Earth. Eight male astronauts (44 ± 7 years of age (mean ± SD); mean mission length: 167 ± 12 days) participated in a standardized supine-to-sit-to-stand test (5 min-30s-3 min) pre- and postflight, and a 3 min thigh cuff occlusion test pre- and inflight with continuous monitoring of heart rate and arterial blood pressure. The arterial baroreflex was not changed inflight as shown by similar reductions in mean arterial pressure (MAP) response to leg cuff deflation (preflight -19 ± 2 mmHg vs. inflight -18 ± 5 mmHg). With the sit/stand test, the nadir of MAP was lower postflight (-17 ± 9 mmHg) than preflight (-11 ± 6 mmHg, p < 0.05). A greater increase in heart rate (25 ± 7; 16 ± 3 bpm) and decrease in stroke volume (-24 ± 11; -6 ± 4 mL) occurred with sit/stand postflight than leg cuffs inflight (p < 0.001). Inflight testing was influenced by elevated cardiac output resulting in a smaller drop in total peripheral resistance. Two of eight subjects exhibited orthostatic hypotension during the postflight stand test; their responses were not predicted by the inflight leg cuff deflation test. These results suggest that the baroreflex response examined by inflight leg cuff deflation was not a reliable indicator of postflight stand responses.