The natural killer (NK) cell is one of the key cells in discriminating major histocompatibility complex (MHC) negative 'missing-self' target tumor cells, and interleukin 2 (IL-2) treatment was effective in inducing NK cell activation. In this study, we tried to clarify how poorly-immunogenic murine B16 melanoma could be discriminated in vivo by creating an IL-2 cDNA-transduced immunogene therapy model (B16/IL-2). In vitro study showed that IL-2 introduction did not induce MHC class I. However, immune cells depleted total tumor digest, which consisted of 90% anti-melanoma MM2-9B6-positive cells that revealed B16/IL-2 strongly, and control tumor cells (B16/mock) partially expressed MHC class I in vivo. In the B16/IL-2 model, NK cell infiltration was 10 times higher than B16/mock (7.6 versus 0.73, p=0.017). In addition, the cell surface of CD69-expressing NK cell population was increased in B16/IL-2, and the interferon gamma (IFNgamma) message level in NK cells was significantly increased in B16/IL-2 (p=0.0359). Interestingly, NK cell depletion in vivo completely abolished MHC class I expression on B16/mock, and decreased MHC class I expression and T-cell infiltration in B16/IL-2. These data suggest that NK cells are not only important for missing-self recognition, but are also crucial for induction of tumor cell MHC molecule expression and play an important role in helping acquired immunity to recognize tumor cells.