Tumor necrosis factor α (TNF-α) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia-reperfusion (IR) liver injury and is associated with activation of nuclear factor κB (NF-κB) and cell cycle entry. We examined the pattern of TNF-α release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low-dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naïve mice, hepatic and plasma levels of TNF-α rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF-α levels, but, during a second prolonged ischemic interval peak, TNF-α values were lower than in naïve mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 μg or 5 μg/kg body weight TNF-α 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF-α pretreatment activated NF-κB DNA binding, STAT3, cyclin D1, cyclin-dependent kinase 4 (cdk4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of “preconditioning” can be simulated by TNF-α injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF-α levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury.