A 50,000-dalton polypeptide has been purified from fractions enriched with neurofibrillary tangles of paired helical filaments from human autopsy specimens of Alzheimer disease and senile dementia of the Alzheimer type. An antiserum to this polypeptide was raised in a rabbit. This antiserum formed an immunoprecipition line with the purified antigen and with human neurotubules in Ouchterlong double-diffusion plates. The reactivity of the anti-paired helical filament protein serum with neurofibrillary tangles was studied by immunof uorescence on cryostat sections of hippocampus from Alzheimer autopsy tissue and by the peroxidase-antiperoxidase technique on paraffin sections of an Alzheimer brain biopsy. The tangles were stained with the antiserum in both systems. Preimmune rabbit serum and unrelated hyperimmune sera, used as controls, did not stain the tangles. These results show that the 50,000-dalton polypeptide purified form the neurofibrillary tangle-enriched fractions is a constituent of Alzheimer neurofibrillary tangles and, perhaps, of the paired helical filaments of which the tangles are composed.