Adaptive immune surveillance by T cells against infections and tumors depends on the presence of antigenic peptides presented by major histocompatibility complex (MHC) molecules. If antigenic tumor‐specific peptides or MHC class I molecules are absent, the adaptive T cell immune response fails. Natural killer (NK) cells seem to complement the specific T cells by recognizing target cells lacking MHC class I (e.g. RMA‐S). The role of perforin, which is crucially involved in T cell and NK cell‐mediated target cell lysis, was evaluated in mice lacking perforin with respect to their capacity to eliminate a syngeneic lymphoid tumor. Here, we show that growth of MHC class I⁻ RMA‐S tumor cells in unprimed mice was controlled by NK cells through perforin‐dependent cytotoxicity.