The haemodynamic and autonomic effects of prolonged exposure to simulated microgravity were assessed non-invasively in seven healthy volunteers completing a 42-day -6 degrees head down tilt. Before, during and after head down tilt, subjects were exposed to moderate excitatory stimuli (mental arithmetic and static handgrip) to gauge possible progressive impairment of pressor responses. Before and after head down tilt, subjects were also exposed to orthostatic stress, to assess influences of simulated microgravity on orthostatic defence. Simple haemodynamics (heart rate and systolic arterial blood pressure), linear (i.e., oscillatory) components of beat-by-beat variability, non-linear properties (i.e., corrected conditional entropy (CCE)) of RR interval variability, and baroreflex slope furnished a non-invasive evaluation of autonomic regulatory mechanisms. Pressor responses to mental arithmetic and to handgrip were markedly impaired after 42 days head down tilt, whereas responses in markers of autonomic regulation were not modified. Standing, performed 8 days after head down tilt to limit the risk of syncope, still induced a variable degree of hypotension, with signs of progressively greater sympathetic activation than before head down tilt. Simulated microgravity-induced reduction of pressor responses, in spite of largely maintained autonomic activation, favours the hypothesis of a peripheral impairment of cardiovascular homeostasis. rights reserved.