Mitochondrial generation of reactive oxygen species (ROS) is increased in mice with fatty livers induced by genetic obesity or chronic consumption of ethanol or methionine/choline-deficient (MCD) diets. Both nuclear and mitochondrial (mt) DNA are targets for ROS-induced damage and accumulate hydroxylated bases, such as 8-oxoG and A*8-oxoG, that introduce mutations that promote cancer, as well as cell death. MYH, the mammalian homolog of the bacterial DNA mismatch repair (MMR) enzyme, MutY, removes A*8-oxoG from mitochondrial and nuclear DNA, reduces 8-oxoG accumulation, and restores genomic stability after ROS exposure. Cumulative damage to mt DNA occurs as fatty liver disease progresses. Therefore, differences in hepatic MYH activity may influence the severity of fatty liver disease. To evaluate this hypothesis, we compared mt H₂O₂ production, MYH expression, oxidative DNA damage and hepatocyte death in healthy mice and different mouse models of fatty liver disease. The results show that diverse causes of steatohepatitis increase mt ROS production, limit repair of mt DNA, and oxidatively damage DNA. However, there are important differences in the DNA repair response to oxidant stress among mouse models of fatty liver disease. Independent of the degree of mitochondrial ROS generation, models with the least MYH exhibit the greatest accumulation of 8-oxoG and the most hepatocyte death. These findings raise the intriguing possibility that inherited or acquired differences in DNA repair enzyme activity may underlie some of the inter-individual differences in fatty liver disease outcomes.