Background/Aims: In liver resection and transplantation ischemia reperfusion injury (IRI) is one of the main causes of organ dys- or nonfunction. Aim of the present study was to determine whether -lipoic acid (LA) is able to attenuate IRI. Methods: Rat livers were perfused with KH-buffer with or without LA (± wortmannin), followed by ischemia (1 h, 37°C) and reperfusion (90 min). Efflux of LDH and PNP and hepatic ATP content were determined enzymatically. Activation of NF-B and AP-1 was examined by EMSA, protein phosphorylation by Western blot. Caspase-3-like activity served as an indicator for apoptotic processes. Animals treated intravenously with 500 µmol LA were subjected to 90 min of partial no-flow ischemia followed by reperfusion for up to 7 d. Results: Preconditioning with LA significantly reduced LDH and PNP efflux during reperfusion in isolated perfused rat livers. ATP content was significantly increased in LA-treated livers. Postischemic activation of NF-B and AP-1 was significantly reduced in LA-pretreated organs. Preconditioning with LA significantly enhanced Akt phosphorylation. It showed neither effect on eNOS nor on Bad phosphorylation. Importantly, simultaneous administration of wortmannin, an inhibitor of the PI-3 kinase/Akt pathway blocked the protective effect of LA on IRI, demonstrating a causal relationship between Akt activation and hepatoprotection by LA. Interestingly, despite activation of Akt, LA did not reduce post-ischemic apoptotic cell death. The efficacy of LA treatment in vivo was shown by reduced GST plasma levels and improved liver histology of animals pretreated with LA. Conclusion: This study shows for the first time that the PI-3 kinase/Akt pathway plays a central protective role in IRI of the rat liver and that LA administration attenuates IRI via this pathway.