This study evaluates whether preconditioning could modulate the injurious effects of tumor necrosis factor (TNF) on liver and lung following hepatic ischemia-reperfusion (I/R) by inhibiting hepatic postischemic TNF release. The inhibition of hepatic TNF release from Kupffer cells with gadolinium chloride (GdCl3) previous to ischemia maintained TNF at control levels, attenuating the increases in transaminases, vascular permeability, and edema associated with hepatic I/R injury. TNF addition reverted this beneficial effect, indicating the implication of the TNF released mainly from Kupffer cells in hepatic I/R injury. Preconditioning prevented hepatic TNF increases, thus attenuating the liver injury, while TNF addition abolished the benefits of preconditioning. Inhibition of nitric oxide (NO) synthesis abolished the effect of preconditioning, whereas GdCl3 addition avoided the injurious effect of NO inhibition. In addition, NO administration before I/R offered similar results to those found in preconditioning, while TNF addition abolished the benefits of NO. Thus, the effect of preconditioning on TNF release after hepatic I/R is mediated by NO. Inhibition of hepatic TNF release from Kupffer cells with GdCl3 prevented both the increase in plasma TNF and the injurious effect in lung seen after hepatic I/R, and these effects were reverted with TNF addition. Preconditioning resulting in reduced hepatic TNF levels prevented the systemic TNF release, thus reducing the lung damage following hepatic I/R. However, TNF addition abolished the protective effect of preconditioning on lung injury. These findings indicate that preconditioning attenuates hepatic postischemic TNF release from Kupffer cells, thus probably reducing the liver and lung injury following hepatic I/R, and that this effect of preconditioning is mediated by NO.