Transfection with c-fos genes of cells of a highly metastatic (H-2K- H-2D+) clone, DI22, of the 3LL carcinoma, causes activation of H-2K gene expression. Experiments were carried out to test whether these transfectants exhibit reduced metastatic competence. Studying II mouse c-fos, 6 mouse c-fos and 2 v-fos transfected clones, we observed that clones expressing high steady-state levels of the fos mRNA also expressed elevated levels of H-2K and H-2D mRNA, and high levels of cell-surface H-2K and H-2D glycoproteins. The transfectants were tested for generation of spontaneous metastasis following intra-footpad inoculation of the tumor cells. Clones expressing high levels of fos and of H-2 antigens, particularly those expressing high levels of cell-surface H-2Kb molecules, showed a reduction of their metastatic competence. Statistical analysis revealed that c-fos transfectants are significantly less metastatic than the parental cells. The molecular mechanisms of c-fos activation of H-2 genes is briefly discussed.