Multiple lines of evidence indicate that the hemostatic system contributes to cancer dissemination. Previous studies have shown that tumor cell-associated tissue factor (TF) expression is a crucial determinant of metastatic potential. Furthermore, we have shown that tumor cell-associated TF supports metastatic potential through mechanism(s) dependent on multiple circulating hemostatic system components, including prothrombin, platelets, fibrinogen and, more recently, fXIII. At least two of these circulating hemostatic factors (platelets and fibrinogen) have been shown to support metastatic potential by impeding the clearance of recently embolized tumor cells by natural killer (NK) cells. It is reasonable to hypothesize that tumor cell-associated TF expression also supports metastatic potential by a mechanism coupled to NK cell function. Here, we used C57BL/6-derived, Ras-transformed tumor cell lines expressing wildtype murine tissue factor (TFWT), a mutant TF lacking the intracytoplasmic portion (TFΔTail), or no tissue factor (TFO) to directly examine the interplay between tumor cell-associated TF and NK cell function in determining metastatic potential. Each of these cell lines was capable of robust, comparable tumor growth in wildtype C57BL/6 mice. Loss of either platelet function or fibrinogen significantly diminished the metastatic potential of TFWT cells, but this effect was entirely abrogated by the concomitant loss of NK cells. Similar results were obtained with TFΔTail cells, indicating that the cytoplasmic portion of TF is not critical to these interactions. To determine if the increase in metastatic potential conferred by tumor cell-associated TF expression is entirely linked to NK cell function, we compared the metastatic potential and early survival of TFWT and TFO cells in mice with and without NK cells. TFOcells rarely formed any visible metastatic foci in mice with intact NK cell function, while TFWT cells were aggressively metastatic. Importantly, TF expression remained a significant determinant of metastatic potential even in mice lacking NK cells. Comparisons of the early fate of TFWT and TFO cells revealed that TF expression was not a determinant of initial tumor cell localization within the lungs. Rather, TF expression supported the sustained adherence and/or survival of tumor cells. Taken together, these data indicate that one mechanism linking tumor cell-associated TF expression to metastatic potential is coupled to circulating hemostatic factors and results in impaired NK cell-mediated clearance of recently established micrometastatic foci. However, TF expression also supports metastasis by at least one additional mechanism that is independent of natural killer cell function.