The effects of ischemic preconditioning on rat liver integrity, as well as the implication of nitric oxide (NO) and adenosine in this process, has been evaluated. Preconditioning before ischemia-reperfusion prevented the increases in alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels, but did not modify blood flow. Adenosine or NO administration previous to hepatic ischemia-reperfusion simulated the effect of preconditioning, whereas inhibition of adenosine or NO synthesis abolished the protective effect of hepatic preconditioning. Nevertheless, inhibition of adenosine and simultaneous administration of NO in preconditioned animals offered similar results to those found in the preconditioned group, indicating that, in the absence of adenosine, NO is able to maintain the preconditioning benefits. It is suggested that, in preconditioning, adenosine stimulates NO production to protect against the injury associated with ischemia-reperfusion.