CEACAM5 and CEACAM6 are overexpressed in many cancers and are associated with adhesion and invasion. The effects of three monoclonal antibodies targeting different epitopes on these antigens (NH₂-terminal [MN-3] and A1B1 domains [MN-15] shared by CEACAM5 and CEACAM6 and the A3B3 domain [MN-14] restricted to CEACAM5) were evaluated in migration, invasion, and adhesion assays in vitro using a panel of human pancreatic, breast, and colonic cancer cell lines, and in the GW-39 human colonic micrometastasis model in vivo. MN-3 Fab′ and MN-15 Fab′ were both effective at inhibiting cell migration. MN-15 Fab′ treatment inhibited invasion, reducing cell penetration through an extracellular matrix (ECM). MN-3 Fab′ also decreased invasion but was less effective than MN-15 Fab′ in four of five cell lines. All three monoclonal antibody (mAb) Fabs decreased adhesion of tumor cells to endothelial cells by 49% to 58%. MN-15 Fab′ but not MN-3 or MN-14 Fabs induced a decrease in adhesion of three of six cell lines to the ECM protein, fibronectin, but adhesion to vitronectin, laminin, collagen-I, and collagen-IV was not affected. In vivo studies showed that treatment with MN-3 Fab′ or MN-15 Fab′ of mice implanted with GW-39 human colonic cancer cells increased their survival (P < 0.025 and P < 0.01, respectively). These studies show that antibody Fabs that target either CEACAM5 or CEACAM6 affect cell migration, cell invasion, and cell adhesion in vitro, and that MN-15 and MN-3 Fabs have antimetastatic effects in vivo, resulting in improved survival of mice with metastases. Thus, blocking the N and A1B1 domains of CEACAM5/CEACAM6 can impede the metastatic process.