Several studies point to the importance of peptides and proteolysis in Alzheimer's disease (AD). Because of its ability to study small proteins and peptides, reverse-phase HPLC was employed to study these species in AD. Cerebellum was chosen for these initial studies because it does not show significant neuronal loss but does show some pathology in AD. Examination of over 600 peptide peaks per case revealed 15 that were elevated in AD. Nine were fragments of hemoglobin, and the remainder included two species of calmodulin, two of myelin basic protein, and one each of 67 kDa neurofilament protein and PEP-19. The cleavage sites on hemoglobin were after hydrophobic residues and immunolocalization was seen preferentially around blood vessel walls and granule cells. The elevation of the non-serum-derived peptides was characteristic of general metabolic changes that occurred in AD cerebellum, and the presence of elevated hemoglobin polypeptides indicated either possible disruption of the blood-brain barrier or selective evasion of it by peptidaceous products. Further studies are required to establish whether hemoglobin fragments have a role in neurodegenerative processes such as AD.