Tumor overgrowth in spite of an ongoing antitumor immune response may be due to a basic immunologic defect in T cell-mediated responses against the potentially immunogenic tumor cells. To further understand T cell-mediated responses in syngeneic tumor-host systems, we have analyzed the interaction of cytotoxic T lymphocytes (CTL) with syngeneic tumor cells and have compared it with CTL-allogeneic tumor cell interaction. The major conclusions of this study are: 1) Syngeneic and allogeneic CTL lyse target cells through a similar mechanism. 2) The reduced reactivity in the syngeneic system is due to the low content of effector cells capable of binding to and killing tumor cells. 3) The avidity of CTL-syngeneic tumor cell binding is lower than CTL-allogeneic tumor cell binding. We suggest that the latter 2 observations result from a low immunogenicity of tumor cells in the syngeneic host.