Immunoreactive beta-endorphin in the third ventricular fluid was measured in response to electrical stimulation of the periaqueductal gray matter in 8 patients with intractable pain during rostral mesencephalic reticulotomy for pain relief. In all patients, marked increase of immunoreactive beta-endorphin was observed. On the other hand, in cases of electrical stimulation of the zona incerta performed during stereoencephalotomy, in 5 patients with involuntary movement, immunoreactive beta-endorphin in the third ventricular fluid did not show any significant change. The authors conclude that the increase of immunoreactive beta-endorphin on electrical stimulation of the periaqueductal gray matter is not a nonspecific response to brain stimulation but a specific response in regard to cerebral localization of endorphins. Direct correlation between pain relief and periaqueductal gray stimulation is also questioned.