A cDNA encoding epitopes present in paired helical filaments (PHF) in Alzheimer's disease has been characterized by DNA sequencing and by immunochemical analysis of the encoded recombinant protein fragment. The cDNA encodes 773 amino acids specific of the rat high molecular weight microtubule-associated protein MAP2. This amino acid sequence is localized in the side arm projection domain of MAP2. An antiserum raised against the expressed fusion protein encoded by this cDNA labels the high molecular weight MAP2 but not the 70 kDa MAP2c abundant in developing brain. This antiserum labels PHF in situ but only a proportion of isolated PHF. In situ hybridization on human brain sections did not demonstrate an increase in mRNA for MAP2 in tangle-bearing neurones. We suggest that the association of this MAP2 fragment with PHF in situ results from posttranslational modifications of MAP2.