Abstract We report that HMGN1, a nucleosome-binding protein that affects chromatin structure and function, affects the growth of N-nitrosodiethylamine (DEN)-induced liver tumors. Following a single DEN injection at 2 weeks of age, Hmgn1tm1/tm1 mice, lacking the nucleosome-binding domain of HMGN1, had earlier signs of liver tumorigenesis than their Hmgn1+/+ littermates. Detailed gene expression profiling revealed significant differences between DEN-injected and control saline–injected mice, but only minor differences between the injected Hmgn1tm1/tm1 mice and their Hmgn1+/+ littermates. Pathway analysis revealed that the most significant process affected by loss of HMGN1 involves the lipid/sterol metabolic pathway. Our study indicates that in mice, loss of HMGN1 leads to transcription changes that accelerate the progression of DEN-induced hepatocarcinogenesis, without affecting the type of tumors or the final total tumor burden of these mice. Implications: Loss of HMGN1 leads to accelerated progression of DEN-induced hepatocarcinogenesis in mice. Mol Cancer Res; 12(1); 82–90. ©2013 AACR.