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Nitric oxide (NO) is a multifunctional messenger in many vertebrates. In the liver, NO was found to play an important but controversial role in injury produced by toxins or sepsis. The purpose of the present investigation was to further characterize the role of NO in hepatocyte oxidative injury. A cellular system formed of immobilized and perfused rat hepatocytes was used to test the ability of the latter to produce endogenous NO after lipopolysaccharide administration in vivo (LPS, 20 mg/kg i.p.) and how hepatocyte functionality competence is modified according to NO level. This cellular system also was used to delineate a relationship between exogenously delivered NO to the perfusion medium as produced by the NO donor, sodium nitroprusside (2.0 and 0.2 mM), and any alteration in the degree of injury as evoked by anoxia/reoxygenation or cumene hydroperoxide (1.0 mM and 0.2 mM). Rat hepatocytes were immobilized in low-gelling agarose and perfused with Williams E medium. Endogenous or exogenous NO was evaluated by measuring the end products of NO (NO2- + NO3-) in the perfusion medium. Functional integrity of hepatocytes was evaluated from lactate dehydrogenase (LD) leakage, urea synthesis in the perfusion medium and lipid peroxides (LP) formation. Normal, anoxia/reoxygenation or cumene hydroperoxide injured hepatocytes did not exhibit measurable NO while LPS-treated hepatocytes produced NO. Apparently, within the present experimental conditions, it seems that there was an inverse relation between the rate of NO produced after LPS administration and the rate of lipid peroxides formed in the hepatocytes. Low concentration of sodium nitroprusside (as NO donor) significantly decreased LD leakage, increased the rate of urea synthesis and increased trypan blue exclusion by hepatocytes in anoxia/reoxygenation or cumene hydroperoxide injured (0.2 mM) cells. Lipid peroxides were decreased by NO in cumene hydroperoxide injured hepatocytes. The present data suggest that NO endogenously produced, or exogenously delivered, has an ameliorative role in mild oxidative liver injury models, but not in severe cases and that inside hepatocytes, there is a very delicate balance between the rate of NO production and its consumption. The disturbance in this balance may be responsible for injury due to the formation of more toxic oxygen species.