The two antisera to paired helical filaments (PHF) and tau, which stained neurofibrillary tangles similarly in tissue section, were characterized. Anti-PHF reacted exclusively with the carboxyl terminal portion of tau, whereas antitau reacted with the amino terminal portion. In the blots of PHF prepared in Sarkosyl (Sarkosyl-PHF), anti-PHF stained an extensive smear from the top to the bottom of the gel, while antitau did not stain this kind of smear but labeled a small amount of intact tau that was bound to Sarkosyl-PHF. An LDS- or SDS-insoluble residue of Sarkosyl-PHF was labeled with anti-PHF, but not with antitau. Antitau-defined epitopes were susceptible to protease, whereas anti-PHF-defined epitopes were unaffected. Based on these observations, we conclude that Sarkosyl-PHF were composed largely of the carboxyl terminal region of tau and accompanied by a small amount of intact tau on their surfaces.