A metastatic variant of a chemically induced lymphoma (ESb) from a DBA/2 mouse was found to activate in syngeneic hosts specific anti-tumor cytolytic T lymphocytes (CTL) which recognized on the tumor a distinct tumor-associated antigen. Upon metastasis of a cloned ESB tumor line from an s.c. site to the spleen, the tumor cells which were originally sensitive to lysis by anti-ESb CTL became specifically immunoresistant. The development of immunoresistant variants after tumor-cell transplantation followed a defined kinetic and organ pattern: they were first detected in the spleen, then also in the liver and in the late stage of tumor progression they were the predominant tumor type in all involved organs. No immunoresistant tumor variants were generated in immunoincompetent animals such as nude (nu/nu) mice. Immunoresistant variants also developed when immunosensitive ESb clones were inoculated into animals specifically preimmunized against ESb. In fact, these variants were the only type of cells eventually growing out from such animals causing death from metastasis in spite of the specific immune status of the host. The change of tumor antigen expression described here differs from antibodyinduced antigenic modulation in that it is genetically transmitted and stable in tissue culture. The immunoresistant tumor variants which did not preexist in the starting, twice-cloned cell population represent a new type of immune escape variant.