Treatment with an antagonist at the neurokinin-1 (NK-1) receptor may alleviate depression, however the brain region(s) in which the NK-1 receptor antagonist exerts its therapeutic effect is unknown. [125I]BH-Substance P was used to measure NK-1 receptors postmortem in cytoarchitectonically defined areas of rostral orbitofrontal cortex (Brodmann's area 47) of subjects with major depressive disorder (n = 12, six females) and psychiatrically normal subjects (n = 11, five females). Six subjects with depression died by suicide. Subjects with depression showed decreased binding to NK-1 receptors across all cortical layers (p = 0.024). The pathophysiology of depression, and the reported therapeutic benefit of NK-1 receptor antagonists, may thus involve NK-1 receptors in prefrontal cortex.