CEACAM6 (CD66c) and CEACAM8 (CD66b) are cell-adhesion proteins onneutrophils that belong to the human carcinoembryonic antigen (CEA)family. CEACAM6 reveals homophilic adhesion and heterophilic adhesionto other CEACAM family antigens including CEACAM8, CEACAM1, and CEA, whereas CEACAM8 exhibits only heterophilic adhesion to CEACAM6. Here, we investigated and compared structural requirements for the homophilicadhesion of CEACAM6 and heterophilic adhesion between CEACAM6 andCEACAM8 at the amino acid level by using CHO transfectants expressingtheir mutant and chimeric proteins. The NH₂-terminal domain(N-domain) of CEACAM6 expressed on a CHO cell was suggested to bind the N-domain of CEACAM6 or CEACAM8 on the opposing cell. Byhomologue-scanning mutagenesis, we found that the locations of thesequences critical for the adhesion of CEACAM6 to itself and to CEACAM8are overlapped and that they are highly similar but not identical tothe locations of the residues previously shown to be essential for thebinding of CEACAM antigens to Opa proteins of pathogenicNeisseriae. Our findings imply that subtle differences inthe N-domain sequences determine the specificity of the CEACAM antigenson neutrophils for interaction with the same or different CEACAMantigens and the bacterial proteins.