The present study was carried out to examine physiological arousal modulation (heart activity and skin conductance), across baseline and cognitive tasks, in females with fragile X or Turner syndrome and a comparison group of females with neither syndrome. Relative to the comparison group, for whom a greater increase in skin conductance was associated with poor arithmetic performance and less risk taking behavior, females with fragile X displayed a minimal increase in heart activity that was nevertheless associated with poor performance on mental arithmetic. In contrast, no arousal-cognitive performance relationship emerged for the group with Turner syndrome. Taken together, our findings suggest that distinct profiles of arousal modulation might be associated with cognitive deficits in these syndrome populations.