Liver regeneration after partial hepatectomy is growth hormone (GH) dependent in rodents, and in C57BL/6 mice, we show that this is a consequence of induction of the potent immunosuppressive protein H2-Bl (homologue of HLA-G in human). We investigated partial hepatectomy in C57BL/6 mice harbouring different GH receptor (GHR) knockin mutants which delete key signalling domains. Striking mortality post-hepatectomy was evident only in mice lacking GH receptor (Ghr-/-), while GHR knockin mice disabled for all GH-dependent JAK2 signalling (Box1-/-), or for GH-dependent STAT5 signalling (Ghr391-/-), showed minimal mortality. Ghr-/- mortality was associated with decreased phospho-JUN expression, and increased apoptosis with elevated NK/NKT and macrophage cell markers. We had identified a set of GH-regulated genes triggered by a novel SRC pathway independent of JAK2, and within this set the Ghr-/- mice exhibited sharply decreased expression of H2-Bl, a key immunotolerance molecule that acts on the inhibitory receptors ILT2 and ILT4. We show H2-Bl is GH regulated in AML12 hepatocyte cells via SRC/JUN. We find that injury-associated innate immune attack by NK/NKT and macrophage cells is instrumental in 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. We identified that GH treatment of GH deficient patients’ results in increased serum HLA-G. Our studies show that GH upregulation of H2-Bl reduces innate immune-mediated apoptosis after partial hepatectomy.