Studies of healthy and clinical populations have suggested valence-specific cortical and subcortical neural systems regulating emotions. In a study of 12 normal volunteers, the 133xenon clearance method for measuring regional cerebral blood flow (CBF) was used to study the effects of experimentally controlled mood states on regional brain activity within superficial cortex. CBF was measured with 254 detectors and bolus infusion during a happy mood induction task, a sad mood induction task, a sex differentiation task, and a resting baseline condition. CBF increased during sad and decreased during happy mood induction, relative to the activated (sex differentiation) and the nonactivated (resting) nonemotional control conditions. Increased CBF during sad mood induction was correlated with greater negative mood changes. Conversely, increased CBF was associated with a stronger subjective experience of positive affect during happy mood induction. This suggests that cortical arousal may serve to intensify the conscious experience of emotion. Heart rate accelerated during happy and sad mood induction and during sex differentiation relative to a pretask baseline condition. Some regional specificity of effects was also observed. The occipital temporal region showed higher overall CBF during sad mood induction than during happy mood induction. The only region that showed specific lateralized changes in CBF which differentiated sad from happy states was the frontal pole, with left CBF being higher during sad and lower during happy mood induction relative to right CBF. For sad mood induction, there were significant regional differences among correlations between CBF and self-ratings. These were attributable to higher negative correlations (i.e., higher CBF correlates with negative self-rating) in midtemporal, occipital temporal, and postcentral regions. These correlations did not vary across the 15 regions for happy mood induction. For sad mood induction, heart rate correlated positively with CBF increase and with negative affect. Correlations were opposite for happy mood induction. The results suggest high cortical and autonomic arousal during negative/sad mood and low cortical and high autonomic arousal during positive/happy mood. They underscore the value of integrating emotional experience with physiologic measures in neuroimaging activation studies.