In vivo inoculation of a low metastatic BW 5147 derived T-cell lymphoma variant into syngeneic mice, had led to the generation of a highly metastatic variant. The shift towards a more metastatic phenotype is accompanied by an increase in major histocompatibility class I H-2Dk antigen expression. This suggests that H-2Dk antigens may control the metastatic potential of BW T lymphoma cells. Our present findings indicate that H-2Dk expression is directly correlated with the metastatic potential of BW cells. We have confirmed such correlation by specifically altering the level of H-2Dk expression by: 1) FACS analysis, 2) IFN-gamma treatment, 3) H-2Dk gene transfection. Cells sorted for low H-2Dk expression had a significantly reduced metastatic potential. Induction of H-2Dk expression on these cells by either IFN-gamma treatment or H-2Dk gene transfection concomitantly led to increased metastasis. We also assessed metastatic potential of BW cells in irradiated, immunocompromised recipients. Our results show that the immune system is implicated and we further tested which immune effectors are involved. In vivo depletion of natural killer (NK) and CD8+ T-cells revealed that the difference in metastatic potential of the H-2Dk variants relies upon an NK-dependent mechanism, whereas CD8+ T-cells are not implicated. Our observations suggest that highly metastatic cells, expressing a high level of H-2Dk antigens are more resistant to NK-cell-mediated cytotoxicity in vivo. We have confirmed our in vivo results by in vitro cytotoxicity assays using poly I:C induced NK and IL-2 activated LAK cells. We conclude that a NK-dependent mechanism accounts for the association between differential H-2Dk antigen expression and metastasis.