Reduction in plasma volume is a major contributor to orthostatic tachycardia and hypotension after space flight. We set out to determine time- and frequency domain baroreflex (BRS) function during preflight baseline and venous occlusion, and post flight orthostatic stress, testing the hypothesis that a reduction in central blood volume could mimic the postflight orthostatic response. In 5 cosmonauts we measured finger arterial pressure non-invasively in supine and upright positions. Preflight measurements were repeated using venous occlusion thigh cuffs to impede venous return and 'trap' an increased blood volume in the lower extremities; postflight sessions were between 1 to 3 days after return from 10-11 day spaceflight. BRS was determined by spectral analysis and by PRVXBRS, a time-domain BRS computation method. Although all completed the stand tests, 2 of 5 cosmonauts had drastically reduced pulse pressures and an increase in heart rate of around 30 bpm or more during standing after space flight. Averaged for all 5 subjects in standing position, high frequency interbeat-interval spectral power or transfer gain did not decrease postflight. Low frequency gain decreased from 8.1 (4.0) preflight baseline to 6.8 (3.4) postflight (P=0.033); preflight with thigh cuffs inflated, LF gain was 9.4 (4.3) ms/mmHg. There was a shift in time-domain determined pulse interval-to-pressure lag, Tau, toward higher values (P<0.001). None of the postflight results were mimicked during preflight venous occlusion. In conclusion, 2 of 5 cosmonauts showed abnormal orthostatic response one and two days after space flight. Overall there were indications of increased sympathetic response to standing, even though we can expect (partial) restoration of plasma volume to have taken place. Preflight venous occlusion did not mimic the postflight orthostatic response.