A previous functional imaging study demonstrated greater female response in the anterior insula and thalamus and left prefrontal activation in men and right prefrontal activation in women during equal heat intensity but unequal pain experience. For the current study, subjective intensities of noxious heat delivered to the back of the right hand were equalized across subjects, and regional cerebral blood flow was recorded by using positron emission tomography. The female subjects required less laser energy before reporting pain, but the difference was not significant. Correlation of regional cerebral blood flow with subjective pain experience in the whole group showed significant bilateral responses in the parietal, lateral premotor, prefrontal, secondary somatosensory, anterior cingulate and insula cortices, as well as the thalamus. There was significantly greater activation in the left, contralateral, prefrontal, primary and secondary somatosensory, parietal, and insula cortices in the male subjects compared with the female subjects and greater response in the perigenual cingulate cortex in the female subjects. Our study is the first to associate consistent pain experience with gender differences in central response. These differences may relate to differential processing of acute pain with implications for clinical disorders that show a female dominance. The subtle behavioral differences and inconsistent findings across studies, however, suggest the need for caution and further experimentation before speculating further.