BACKGROUND/AIMS: Investigation of apoptosis is pivotal in searching for mechanisms that eliminate colon cancer cells getting trapped in liver sinusoids at the time of surgical removal of the primary tumor. This study focuses on nitric oxide (NO), Fas/FasL and the involvement of interferon-gamma (IFNgamma) in liver sinusoidal endothelial cells (LSECs) and in the colon carcinoma cell line CC531s. METHODS: Apoptosis was quantified and visualized in vitro by specific DNA fragmentation, specific staining and electron microscopy. In vivo experiments were also conducted. RESULTS: In co-cultures of LSECs with CC531s, apoptosis of CC531s was observed only when they were pre-treated with IFNgamma, and was unaffected by blocking the Fas/FasL pathway. However, LSECs continuously produced NO, and apoptosis was inhibited by NO-inhibitors (NMMA and dexamethasone). When IFNgamma-sensitized CC531s were injected into rats, liver weight was lower, in contrast to control conditions where liver weight was higher. CONCLUSIONS: (i) LSECs induce apoptosis in IFNgamma-sensitized CC531s in vitro; (ii) LSECs express FasL; (iii) Fas on CC531s becomes active after IFNgamma-treatment; however, (iv) blocking the Fas/FasL pathway had no effect; (v) apoptosis was inhibited by NO-inhibitors; (vi) the immune system uses this IFNgamma-activated pathway to support LSECs in killing tumor cells.