Using two monoclonal antibodies, tau-1 and PHF-1, and a sequential staining method combining double-labeling immunofluorescence and Bielschowsky silver staining, we have demonstrated the presence of two populations of dystrophic neurites (DNs) with distinct immunocytochemical and argentophilic characteristics. Tau-1 and PHF-1 immunoreactivity were co-localized in many DNs. However, approximately 20% of the DNs were immunoreactive for PHF-1 only. PHF-1 single-labeled DNs were not visible or very weak with Bielschowsky silver stain. Of DNs continuous with neurofibrillary tangles (NFTs), tau-1/PHF-1 double-labeled DNs were continuous with intracellular NFTs only, while PHF-1 single-labeled DNs were continuous with extracellular NFTs only. Furthermore, the population of DNs that cluster around extracellular NFTs is different from those that cluster around or within senile plaques. The combined use of tau-1 and PHF-1 immunocytochemistry may provide a more accurate indication of the number of extracellular DNs and extracellular NFTs, which may aid in the diagnosis of severe and advanced AD cases.