Reg2/RegIIIβ is the murine homologue of the human secreted HIP/PAP C‐type lectin. HIP/PAP transgenic mice were protected against acetaminophen‐induced acute liver failure and were stimulated to regenerate post‐hepatectomy. To assess the role of Reg2, we used Reg2−/− mice in a model of fulminant hepatitis induced by Fas and in the post‐hepatectomy regeneration. Within 4 hours of J0‐2 treatment (0.5 μg/g), only 50% of the Reg2−/− mice were alive but with an increased sensitivity to Fas‐induced oxidative stress and a decreased level of Bcl‐xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl‐xL. In Reg2−/− mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S‐phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL‐6/STAT‐3 activation and mito‐inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild‐type mice, Reg2 could mediate the TNF‐α/IL‐6 priming signaling by exerting a negative feed‐back on STAT3/IL‐6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas‐induced oxidative stress and delayed liver regeneration with persistent TNF‐α/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver. (HEPATOLOGY 2006;44:1452–1464.)