Recent characterization of the genomic structure of carcinoembryonic antigen (CEA) is consistent with that of a cellular adhesion molecule. To examine this function in colorectal cancer, the adherence of cell lines to microtiter wells coated with CEA and well-described adhesive molecules was determined. The CEA-positive cell line LoVo and the CEA-devoid cell line H-Meso-1 did not differ in adherence to the extracellular matrix proteins laminin, collagen and fibronectin, whereas LoVo cells adhered to CEA (10-mu-g/well) in a specific manner (43% bound cells vs. 1.5% bound cells with BSA or alpha-acidglycoprotein controls, P < 0.01) while H-MESO-1 showed no adhesion to CEA (< 0.6% bound cells). This adhesion of LoVo cells to CEA was not affected by co-incubation of cells with EDTA, sodium azide, or at 23-degrees-C. However, the CEA to CEA adhesive interaction was inhibited by a monoclonal antibody directed against an epitope in the N-terminal domain of the CEA molecule, and decreased by enzymatic removal of CEA from the LoVo cell membrane. The extent of adhesion to immobilized CEA by four CEA-producing cell lines (LoVo, HT29, LS174T and LS174-S), correlated with membrane CEA expression as determined by FACS analysis. The results of these experiments add support to the concept that CEA may function as a specific homotypic cellular adhesion molecule for colorectal cancer cells.