Abstract--During everyday life, gravity constantly stresses the cardiovascular system in upright humans by diminishing venous return. This decreases cardiac output and induces systemic vasoconstriction to prevent blood pressure from falling. We therefore tested the hypothesis that entering weightlessness leads to a prompt increase in cardiac output and to systemic vasodilatation and that these effects persist for at least a week of weightlessness in space. Cardiac output and mean arterial pressure were measured in 8 healthy humans during acute 20-s periods of weightlessness in parabolic airplane flights and on the seventh and eighth day of weightlessness in 4 astronauts in space. The seated 1-G position acted as reference. Entering weightlessness promptly increased cardiac output by 29±7%, from 6.6±0.7 to 8.4±0.9 L min^-1 (mean±SEM; P=0.003), whereas mean arterial pressure and heart rate were unaffected. Thus, systemic vascular resistance decreased by 24±4% (P=0.017). After a week of weightlessness in space, cardiac output was increased by 22±8% from 5.1±0.3 to 6.1±0.1 L min^-1 (P=0.021), with mean arterial pressure and heart rate being unchanged so that systemic vascular resistance was decreased by 14±9% (P=0.047). In conclusion, entering weightlessness promptly increases cardiac output and dilates the systemic circulation. This vasorelaxation persists for at least a week into spaceflight. Thus, it is probably healthy for the human cardiovascular system to fly in space.