TA3/Ha mammary carcinoma cells form liver metastases upon intraportal injection. We have studied the interaction between these cells and hepatocytes that is likely to be important for liver metastasis formation. We show that the integrin alpha 6 beta 4, which is highly expressed on TA3 cells, is involved in this interaction. Fab fragments, generated from a polyclonal serum against TA3 cells, inhibited TA3-hepatocyte adhesion. By affinity purification on purified alpha 6 beta 4, we isolated alpha 6 beta 4-specific Fab fragments from this anti-TA3 serum. These antibodies were highly specific for alpha 6 beta 4, as demonstrated by Western blot analysis and immunoprecipitation, and inhibited TA3-hepatocyte adhesion. This shows that alpha 6 beta 4, which thus far has only been implicated in cell-matrix adhesion, can also mediate interactions with cell surfaces. Our results suggest that the high levels of alpha 6 beta 4 often expressed by metastatic carcinoma cells contribute to liver metastasis formation.