Murine Ly‐6 is a molecule expressed by various cells, including several types of hematopoietic cells such as pluripotent stem cells, and activated T cells. Ly‐6 is also expressed on tumor cells originating from a variety of tissues. Preliminary observations suggested that the expression of Ly‐6A/E is up‐regulated on highly tumorigenic variants of polyoma‐virus(PyV)‐transformed BALB/c 3T3 cells as compared with weakly tumorigenic variants. On the basis of these observations, we sorted PyV‐transformed A3C cells or DA3 mammary adenocarcinoma cells into stable sub‐populations expressing high or low levels of membrane or mRNA Ly‐6A/E. In vivo studies indicated that the high‐Ly‐6A/E‐expressing cells in both tumor systems expressed a considerably more malignant phenotype (higher efficiency in local tumor production as well as in lung colonization) than low‐Ly‐6A/E expressors. Since the high‐Ly‐6A/E expressors did not exhibit any growth advantage in vitro over low Ly‐6A/E expressors, we concluded that interactions of the former cells with micro‐environmental factors operating in vivo (e.g., Ly‐6A/E ligands) conferred upon these cells a highly malignant phenotype. Apart from the difference in Ly‐6A/E expression, no other phenotypic characteristics distinguished highly from weakly malignant tumor cells. Similarly to T cells, where antibodies to Ly‐6 transduce (or co‐transduce) a proliferative signal, antibodies to Ly‐6A/E were found to transduce a mitogenic signal to high‐Ly‐6A/E‐expressing tumor cells but not to low‐Ly‐6A/E expressors. Taken together, these results show that Ly‐6A/E expression is directly or indirectly associated in vivo with a highly malignant phenotype of 2 types of non‐lymphoid murine tumors.