Cytotoxicity and production of cytokines are two important functions of NK cells. These two different NK functions were studied in a syngeneic rat model in relation to MHC class I expression. We focussed on the mechanism by which NK cells modulate MHC class I expression on target cells and how this interferes with NK cell-mediated lysis. Using transfection experiments an inhibitory role on NK cell cytotoxicity for expression of target cells of RT1.A, rat MHC class I, was found. Co-culturing syngeneic tumor cells and NK cells resulted in enhanced MHC class I expression on the surviving tumor cell fraction, which was less susceptible to NK lysis. Increased tumor cell MHC class I was due to production of a soluble factor by NK cells, most likely interferon gamma. The regulatory function of NK cells shows here, that the enhancing of MHC class I expression on tumor cells in vitro and in vivo, results in downregulation of their target cell killing, but at the same time may facilitate the cytotoxic T cell function.