Missing‐self‐reactivity can be mimicked by blocking self‐specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab‐mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self‐tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H‐2^b) NK cells were blocked with F(ab')₂ fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence‐labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK cell‐dependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab')₂ for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab')₂ together with high dose IL‐2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I‐expressing tumors.