Objective: The authors explored the question of whether acute, transient changes in mood are reflected in activation of discrete neuronal systems in the human brain. Method: Using positron emission tomography, they measured the regional cerebral blood flow (CBF) of seven psychiatrically healthy subjects under two conditions. During the control condition the subjects were resting with their eyes closed. During the active condition, with their eyes still closed, they were asked to imagine or recall a situation that would make them feel very sad. They were explicitly asked to experience sadness and to avoid any feelings of anger or anxiety. Results: There were significant differences in regional CBF measured during the control condition and during the active condition, particularly in the inferior and orbitofrontal cortices. Women showed bilateral inferior and orbitofrontal activation, but men displayed predominantly left-sided activation in these areas. Conclusions: The authors conclude that the inferior and orbitofrontal cortices play an important role in normal emotional cognitive processes.