Background: Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Material and methods: Lean mice and mice made obese through feeding of a high fat, hyper-caloric diet underwent 70% or 80% hepatectomy. Results: After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (p<0.05). Gene expression profiling showed decreased Epidermal Growth Factor Receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and pEGFR decreased with increasing percentage body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation and improving survival after 80% resection. Conclusions: loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation.