We have determined the epitope for Tau 2, a monoclonal antibody that intensely stained tangles, plaque neurites, and curly fibers in the tissue section, and strongly labeled bovine tau, but only very weakly labeled human tau on the blot. The epitope has been localized to Ala95 through Ala108 of bovine tau. Ser101 is critical for Tau 2 reactivities; the replacement of Ser by Pro, which is found in rat, mouse, and human tau, brings about very weak Tau 2 reactivities. The strong Tau 2 staining of tangles and its effective absorption with a synthetic Ser peptide (Ala95 through Ala108) suggest that the tau in paired helical filaments takes a Ser conformation, rather than a Pro conformation, in its amino-terminal portion.