BACKGROUND During spaceflight, changes in the cardiovascular system and in pulmonary mechanics take place but no apparent impairment of respiratory function occurs. However, little is known about the first hours in microgravity. HYPOTHESIS The changes occurring at the same time in the cardiovascular and pulmonary systems could interact and lead to a transient impairment of blood gases at the onset of microgravity. METHODS Cardiovascular and respiratory changes were studied during 6 degrees head-down tilt (HDT), a now well-known method for simulation of microgravity. After a baseline standing position, 10 men were exposed to 4 h of 6 degrees HDT. Hemodynamic parameters were measured by thoracic electrical bioimpedance. Ventilatory parameters were studied by spirographic measurements and mass spectrometer analysis of expired gases. Arterial blood parameters were analyzed by specific electrodes. RESULTS Immediately after tilting, stroke volume and cardiac output increased, as measured by thoracic bio-impedance, while heart rate and thoracic fluid index decreased. Blood gas analysis showed hypercapnia, acidosis and a tendency to hypoxia. These changes were related to hypoventilation shown by the decrease in minute ventilation. After usually less than 30 min, all the parameters reached a steady state. Return to the standing position provoked reverse variations with orthostatic intolerance in 4 subjects. CONCLUSION Marked changes in both the cardiovascular and respiratory systems occur within the first minutes of HDT (i.e., transition to simulated microgravity).