GRB2-associated-binding protein 2 (Gab2) deletion has a preventive effect of on chronic liver inflammation and hepatocellular carcinoma. This study was aimed to elaborate Gab2-initiated immunoregulation during hepatocarcinogenesis. Compared to wild-type group, liver-specific overexpression of Gab2 mice (L-Gab2) displayed early hepatocarcinogenesis after 5-month diethylnitrosamine (DEN) induction, and accelerated tumor growth after 9-month DEN challenge. More myeloid-derived suppressor cells (MDSCs) were observed in DEN-challenged L-Gab2 mice than that in DEN-treated wild-type mice. Additionally, MDSCs activation-induced tumor angiogenesis capability and immunosuppression function were exceedingly activated in DEN-exposed L-Gab2 mice, which reflected in the increased platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial growth factor (VEGF), and the decreased cytotoxic T lymphocytes. Mechanistically, DEN-challenged L-Gab2 mice produced more IL-6, and IL-6 depletion significantly deprived Gab2-overexpression-mediated tumor-promotion phenomena, accompanied by the impairment of MDSCs-initiated immunosuppression function. MDSCs isolated from IL-6-depleted L-Gab2 mice or inactivating MDSCs partly restored the immune function of cytotoxic T cells. Of note, MDSCs gene signatures had a significant association with the increased Gab2 or IL6 in hepatoma specimens. Collectively, L-Gab2 mice accelerated hepatoma progression possibly through activating IL-6-initiated the activation of MDSCs. This study provides a novel insights for exploring the role of Gab2 in autoimmune tolerance during hepatocarcinogenesis.