We investigated sex differences in the resting-state neural correlates of Openness to Experience, a universal personality trait defined by cognitive flexibility, attention to feelings, creativity, and preference for novelty. Using resting-state positron-emission tomography from 100 older individuals (>55 years of age), we identified associations between Openness and resting-state regional cerebral blood flow that replicated across 2 assessments of the same sample, approximately 2 years apart. Openness correlated positively with prefrontal activity in women, anterior cingulate activity in men, and orbitofrontal activity in both sexes, which suggests that areas linked to cognitive flexibility (women), monitoring processes (men), and reward and emotional processing (both) underlie individual differences in Openness. The results challenge the implicit assumption that the same trait will rely on the same neural mechanisms across all who express it.