NK cells kill a wide variety of tumor cells, but usually leave normal cells intact. It was earlier reported that low class I HLA expression can be one of the factors that render target cells relatively susceptible to NK lysis. In this contribution, we show that in human melanomas the class I HLA expression is down-modulated by high expression of transfected c-myc oncogenes. The extent of down-modulation depended on the level of c-myc expression in a dose-dependent way. Taken together, these data suggested to us that one of the results of high c-myc expression could be the induction of a NK susceptible phenotype in melanoma cells. Therefore, we analyzed the effect of c-myc on NK susceptibility. We have found that high expression of transfected c-myc genes indeed converts the melanoma cell lines from poor into good targets for NK cells. IFN-gamma was used to restore the class I HLA expression of the c-myc transfectants, and the resulting cells showed a decreased NK susceptibility. These results suggest the possibility that the c-myc-induced NK susceptibility is mediated by the reduction of class I HLA expression.