Preconditioning with noble gases serves as an effective strategy to diminish tissue injury in different organs. The aim of this study was to investigate the influence of pretreatment with the nonanesthetic noble gas helium on hepatic injury after warm ischemia and reperfusion (IR) in comparison to ischemic preconditioning (IPC). Anesthetized and ventilated rats were randomized into six groups (n = 8/group): sham: after laparotomy, the portal triad was exposed without clamping; IPC was performed with 10 min of partial liver ischemia and 10 min of reperfusion; HePC: three cycles of 5 min with inhalation of helium 70 vol% and intermittent washout; IR: 45 min of ischemia followed by 240 min of reperfusion; IPC-IR: IPC followed by hepatic IR; HePC-IR: pretreatment with helium 70 vol% followed by hepatic IR. Hepatic injury was evaluated by measurement of serum enzymes aspartate aminotransferase and alanine aminotransferase. Hepatic mRNA expression and serum levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were measured with real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Myeloperoxidase in liver tissue was assessed spectrophotometrically as a marker of neutrophil accumulation. mRNA levels of heme oxygenase 1 in liver tissue were assessed to investigate a protein of the most abundant protective system in the liver. Aspartate aminotransferase and alanine aminotransferase serum activities increased after hepatic IR (sham vs. IR; P < 0.05). The serum levels of liver enzymes after IR were significantly diminished with IPC (P < 0.05), whereas helium pretreatment had no effect. mRNA expression of TNF-α increased in all groups except IPC-IR compared with sham, whereas mRNA expression of IL-10 increased only after helium pretreatment. Serum levels of IL-10 were not affected by any intervention, whereas serum levels of TNF-α and liver myeloperoxidase were increased after IR, but not after HePC-IR. In conclusion, pretreatment with inhaled helium does not attenuate hepatic injury after warm IR of the liver, although there is evidence for a modulation of the inflammatory response.