Previous work has shown that the echinoderm microtubule-associated protein (EMAP) was a unique MAP with little sequence similarity with the brain MAPs. The purpose of this study was to determine whether there were any small domains within EMAP that were shared by the mammalian brain MAPs, MAP-2, and tau. It is reported here that EMAP and the heat-stable MAP-2 and tau share antigenic determinants. A polyclonal antisera, raised against SDS-PAGE denatured EMAP, reacted strongly with both MAP-2 and tau on Western blots. In addition, a detailed sequence comparison, using a window of 5 amino acids at a time, revealed several short domains with approximately 20 residues that shared sequence similarity. The regions of sequence similarity were all located in regions implicated in microtubule binding, suggesting that EMAP and the mammalian brain MAPs may share short structural and functional domains.