Following sequential interactions between activated syngeneic M phi s and 3LL tumor cells, stable M phi-resistant 3LL variants were isolated. Unlike the unselected 3LL cells, these M phi-selected variants were relatively resistant to the cytostatic and cytolytic activity of activated effector M phi s. Such M phi-resistant 3LL variants evade the M phi tumoricidal activity by at least two mechanisms. Firstly, they manifest a reduced susceptibility towards M phi-related cytotoxins such as TNF. Secondly, they actively suppress the cytotoxic potential of M phi s through secretion of M phi-inhibitory factors. The resistance of the 3LL variants to M phi effector cells in vitro was reflected in vivo by a higher tumorigenic and metastatic potential. No strict correlation was found between the NK sensitivity of M phi-resistant and M phi-sensitive 3LL cells and their metastatic ability. Hence, activated tumoricidal M phi s may play a central role in either the elimination or selection of neoplastic cells.