Several studies indicate that the incidence of orthostatic intolerance (OI) among female astronauts is significantly higher than compared to their male counterparts. Our lab has previously demonstrated that astronauts who are orthostatically tolerant after spaceflight develop an increase in central arterial stiffness during spaceflight. We hypothesize that the arterial stiffness of female astronauts does not increase, or increases insufficiently, during spaceflight. This may explain, in part, the gender difference in the incidence of OI. We explored this hypothesis by using previously collected hemodynamic data from astronauts as well as from subjects subjected to -6° head-down tilt bedrest. Female astronauts had a non-significant decrease in arterial stiffness following spaceflight (0.08 ± 0.066 mmHg/ml N=11, P=0.2405) in contrast, male astronauts demonstrated a significant increase in arterial stiffness (0.10 ± 0.04 mmHg/ml N=46, P=0.0145). Female bedrest subjects had an insignificant increase in arterial stiffness during bedrest, (0.17±0.059 mmHg/ml, p=0.0973, N=3); however, it was not as great as the increase in arterial stiffness developed by the male subjects (0.33±0.056 mmHg/ml, p=0.01, N=4). Thus, it is apparent that there is a gender difference in the arterial stiffness response to microgravity exposure. This gender-based differential arterial stiffness response may explain, in part, the disparity of microgravityinduced OI incidence between the genders.