The present study evaluates the effect of ischemic preconditioning on interleukin-1 (IL-1) and interleukin-10 (IL-10) generation following hepatic ischemia/reperfusion (I/R) in normal and steatotic livers as well as the role of nitric oxide (NO) in this process. Increased IL-1 and IL-10 levels were observed in normal livers after I/R. Steatotic livers showed higher IL-1 levels than normal livers, and IL-10 at control levels. The injurious role of IL-1 and the benefits of IL-10 on hepatic I/R injury was shown with the use of IL-1 receptor antagonist (IL-1ra), anti-IL-10 polyclonal antibody against IL-10 (anti-IL-10) and exogenous IL-10. The effective dose of these treatments was different in both types of livers. Preconditioning prevented IL-1 release and increased IL-10 generation after I/R in normal and steatotic livers. IL-1 or anti-IL-10 pretreatments reversed the benefits of preconditioning. IL-1 action inhibition in a preconditioned group that was pretreated with anti-IL-10 did not modify the benefits of preconditioning. In addition, anti-IL-10 pretreatment in the preconditioned group resulted in IL-1 levels comparable to those observed after I/R. NO inhibition eliminated the benefits of preconditioning on IL-10 release, IL-1 levels, and hepatic injury. In conclusion, preconditioning, through IL-10 overproduction, inhibits IL-1 release and the ensuing hepatic I/R injury in normal and steatotic livers. IL-10 generation induced by preconditioning could be mediated by NO. (HEPATOLOGY 2004;39:688 -698.