Dsk5 mice have a gain-of-function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-week old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared to those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared to +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and non-parenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice, but not in post-weaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of low-density lipoprotein receptor (LDLR), no change in proprotein convertase subtilisin/kexin type 9 (PCSK9), and a markedly increased fatty acid synthase (FAS) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA R. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed.Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.