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Gender is an important biological determinant of vulnerability to psychosocial stress. We used perfusion based functional magnetic resonance imaging (fMRI) to measure cerebral blood flow (CBF) responses to mild to moderate stress in 32 healthy people (16 males and 16 females). Psychological stress was elicited using mental arithmetic tasks under varying pressure. Stress in men was associated with CBF increase in the right prefrontal cortex (RPFC) and CBF reduction in the left orbitofrontal cortex (LOrF), a robust response that persisted beyond the stress task period. In contrast, stress in women primarily activated the limbic system, including the ventral striatum, putamen, insula and cingulate cortex. The asymmetric prefrontal activity in males was associated with a physiological index of stress responses—salivary cortisol, whereas the female limbic activation showed a lower degree of correlations with …