Neuropeptide Y (NPY) is one of the most abundant and phylogenetically best conserved peptides in the mammalian central and peripheral nervous system where it plays an important role in the regulation of cardiovascular, metabolic, endocrine, immunological and cognitive functions. In a prospective study we determined neuropeptide Y-like immunoreactivity (NPY-LI) in cerebrospinal fluid (CSF) and plasma of 95 HIV-seropositive (n = 49) or seronegative (n = 46) patients who underwent diagnostic CSF examination. CSF and plasma NPY-LI but not noradrenaline concentrations were higher in seropositive than in seronegative patients indicating that raised levels of NPY-LI did not result from a non-specific activation of the sympathetic nervous system. Increased CSF NPY-LI was positively correlated with the degree of HIV encephalopathy (P < 0.01, Kruskal-Wallis test). Inflammatory disorders of the central nervous system and dementia due to other causes in HIV-seronegative patients were not associated with increased CSF NPY-LI. Our data suggest that increased CSF NPY-LI is a relatively specific phenomenon of HIV encephalopathy and may be involved in the pathogenesis of HIV-related neurological dysfunction. The links between retroviral infection and increased expression of neuropeptide Y and their pathophysiological implications remain to be determined.