Patients suffering from spider phobia were studied with measurement of regional cerebral blood flow (rCBF) when they were looking at a video recording of living spiders. Six patients were studied before and after cognitive psychotherapy with successful outcome in all cases. On each occasion rCBF was measured under 3 conditions: during rest, during exposure to a video recording of neutral nature scenery, and finally while the patient watched a recording of living spiders. The patients who managed to control their emotional reactions without panicking during spider exposure before treatment showed an rCBF increase in prefrontal cortex, more pronounced in the right hemisphere. Following successful treatment, these patients showed an rCBF decrease in this region. In contrast, patients who reported panic during the initial spider exposure showed hypoactivity in the frontal cortex at that time, and then showed an increase in prefrontal rCBF in the spider challenge after cognitive therapy. The psychological improvement from cognitive therapy thus appears to be associated with activation of prefrontal cortex that varies closely with the demands for self-regulation of emotional reactivity.