The distribution of pro-opiomelanocortin (beta-endorphin, adrenocorticotropic hormone, and 16-K) neurons and fiber projections was evaluated immunocytochemically in 50-mu thick cryostat sections of human diencephalon and midbrain. Specific attention was focused upon regions in which deep brain stimulation has been most effective in the relief of selected chronic pain syndromes. This study revealed a remarkable, nearly point-to-point correlation between clinically effective stimulation sites and the distribution of pro-opiomelanocortin fibers in the human brain. Of particular interest was the dense innervation of the periventricular stratum along the third ventricle, the parafascicular centromedian region of the thalamus, and the periaqueductal gray matter of the midbrain. This study provides anatomical support for the hypothesis that beta-endorphin-containing neuronal systems may contribute to stimulation analgesia in the human.