In this study we demonstrate enhanced Kupffer cell (KC) cytotoxicity against several colorectal cell lines by activation of KC and by modulation of the targets (SW948, WiDR, HT29, and SW620) with IFN-gamma. We demonstrated that soluble TNF-alpha had no effect on these tumor cells, while cytotoxicity against SW948 and WiDR was blocked by anti-TNF-alpha. Experiments using a transwell system stressed the importance of close intercellular contact for this process. Anti-IL-1 did not inhibit cytotoxicity against SW948. Modulation of HT29, WiDR, and SW948 by IFN-gamma (500 U/ml) induced a significant increase in cytotoxicity. We conclude that cell-associated TNF-alpha may be responsible for KC cytotoxicity against SW948, a process requiring close intercellular contact. WiDR is only partly lysed by a TNF-alpha-dependent mechanism, whereas HT29 is not. Furthermore, IFN-gamma is involved in the regulation of tumor susceptibility.