We previously found that cell surface molecules of approximately 70, approximately 35, approximately 32, approximately 22, and approximately 14 kDa from liver-metastatic murine RAW117 large-cell lymphoma cells bound to target liver microvessel endothelial cells. Isolation and sequencing of the approximately 35-kDa component revealed it to be annexin II, a Ca(2+)-binding molecule involved in cytoskeletal and membrane interactions. Annexin II antibodies inhibited the adhesion of RAW117 tumor cells to live or fixed liver endothelial cells, and purified tumor cell surface fractions containing the approximately 35-kDa component inhibited partially RAW117 cell-endothelial cell adhesion, suggesting a role for annexins in tumor cell-endothelial cell adhesion. In the present study we identified the 70-kDa cell surface component that binds to hepatic sinusoidal endothelial cells in a Ca(2+)-dependent manner as annexin VI. Cytofluorographic analysis indicated that annexin VI was expressed on the cell surface in slightly higher amounts on highly metastatic RAW117 cells, and it was not removable by EDTA treatment. Anti-annexin VI antibodies inhibited the adhesion of RAW117 cells to fixed or unfixed murine hepatic sinusoidal endothelial cells by approximately 40%, indicating a role for annexin VI in mediating a portion of the Ca(2+)-dependent RAW117 cell adhesion to target liver microvessel endothelial cells.