Objectives: The cause of hypocretin cell loss in human narcolepsy–cataplexy is unknown but has been suggested to be neurodegenerative in nature. To test this hypothesis, we evaluated the remaining hypocretin cells in human narcolepsy brains for the presence of aggregated protein inclusions, gliosis, and inflammation. Methods: Brains were examined by routine histologic methods for potential comorbid neurodegenerative diseases and through immunohistochemical screening for protein inclusions in the hypothalamus. Hypothalamic sections of 4 subjects with narcolepsy and 5 nonneurologic controls were examined immunohistochemically with antibodies against ubiquitin (a marker of aggregated protein), allograft inflammatory factor 1 (AIF1, a microglial activation marker), glial fibrillary acidic protein (GFAP, a reactive astrocytic marker), and hypocretin. Hypothalami of subjects with narcolepsy were additionally examined for the presence of known components of protein aggregates (tau, α-synuclein, amyloid β, and TDP-43). Results: Hypocretin cells were markedly decreased in all 4 subjects with narcolepsy. Ubiquitinated inclusions were not observed in the total of 96 remaining hypocretin cells in these subjects. Further, we noted that even in patients with dementia neuropathology, the lateral hypothalamic hypocretin area was spared from ubiquitinated inclusions. AIF1 and GFAP staining in the perifornical area was unremarkable. Conclusions: Our findings suggest that hypocretin cell loss does not involve ubiquitinated inclusions, the hallmark of most neurodegenerative diseases. The lack of increased markers of inflammation also argues against a progressive and continuous neurodegenerative process. GLOSSARY (AD) = neuropathologically consistent with Alzheimer disease; AIFI = allograft inflammatory factor 1; CERAD = Consortium to Establish a Registry for Alzheimer's Disease; DAB = diaminobenzidine; Fx = fornix; GFAP = glial fibrillary acidic protein; IgG = immunoglobulin G; LBD = Lewy body disease; NA = not available; NFT = neurofibrillary tangle; PBS = phosphate-buffered saline; PLM = periodic leg movement; PMI = postmortem interval; PSG = polysomnography; REML = REM latency; SL = sleep latency; SOREMP = sleep onset REM period; 3V = third ventricle.