The susceptibility to natural killer (NK) cell-mediated cytotoxicity of 20 cell lines obtained from human solid tumors and their class I histocompatibility antigen (HLA) levels were studied in an attempt to determine whether major histocompatibility complex (MHC) products expressed on cells derived from human solid tumors influence NK susceptibility. The effect of interferon-gamma (IFN-gamma) treatment on these elements was also analyzed. The MHC class I (HLA-ABC, HLA-A and HLA-B) antigen levels and degree of NK lysis were very heterogeneous and no correlation was found on comparison. After treatment with IFN-gamma a marked decrease in NK susceptibility was observed in all the cell lines, including the control line K-562. However, the level of HLA class I expression was not modified in any of the lines with the exception of the K-562, which increased. In some cell lines the expression of HLA class I-like antigens. CDla, b and c, was also measured before and after IFN treatment; however, no correlation was found between CD1 levels and NK susceptibility. Consequently, from our results it is possible to conclude that HLA class I antigens do not play a decisive role in NK susceptibility of cell lines derived from human solid tumors and to suggest that molecules which are not HLA class I antigens but IFN-gamma inducible may confer NK resistance to these lines.