The regional distribution of neuropeptide Y-like immunoreactivity (NPY-IR) in the human hypothalamus has been determined using a highly specific immunoradiometric assay. Hypothalami were removed during postmortem examination from 19 subjects. The pituitary stalk and 11 anatomically defined nuclei and areas were microdissected from one or both sides of each hypothalamus. NPY-IR was detectable in the acid extracts of tissue samples prepared from all the hypothalamic regions studied, with the highest concentrations being found in the infundibular nucleus (325 ± 53 fmol/mg wet weight of tissue) and the ventromedial nucleus (217 ± 22 fmol/mg). For the 11 subjects where both sides of the hypothalamus were dissected, values obtained for the areas in one half showed a good degree of symmetry with the corresponding areas on the contralateral side. The infundibular nucleus exhibited the greatest range of values (72–1,137 fmol/mg). Interestingly, variations in other parts of the hypothalamus were observed to parallel those of this nucleus. Expressed as correlation coefficients (r), levels in the infundibular nucleus appeared to be most closely related to those of the ventromedial nucleus (VM; r = 0.89) and paraventricular nucleus (PV; r = 0.84). In addition, retrospective analysis of the clinical histories showed that all patients with very high NPY levels in the infundibular nucleus (621.0 ± 107.7 fmol/mg; n = 8) had suffered from respiratory failure or severe dyspnea of at least 10 days duration prior to death. The remaining patients (166.7 ± 17.1 fmol/mg; n = 11) had either died 48 h from the onset of cardiorespiratory difficulties or of unrelated causes. In the patients with raised concentrations in the infundibular nucleus, correspondingly high levels of NPY were also observed in the PV and VM nuclei, suggesting that functional changes in these NPY pathways may be the result of prolonged respiratory dis