Background and Aims: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. Approach and Results: PHx was performed on C57BL/6 mice lacking GHR (Ghr−/−), disabled for all GH-dependent Janus kinase 2 signaling (Box1−/−), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391−/−), and wild-type littermates. C57BL/6 Ghr−/−mice showed striking mortality within 48 hours after PHx, whereas Box1−/− or Ghr391−/− mice survived with normal liver regeneration. Ghr−/− mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2–independent, SRC family kinase–dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr−/− mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr−/− backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. Conclusions: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.