BACKGROUND & AIMS: Metabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high-fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. METHODS: Female and male C57BL/6J mice were fed a fructose-palmitate-cholesterol (FPC)-NASH diet RESULTS: The FPC-NASH diet-induced metabolic dysfunction in both female and male mice, with females exhibiting more severe hepatic steatosis ( CONCLUSIONS: Molecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female individuals in MAFLD/MASH studies and clinical trials. IMPACT AND IMPLICATIONS: Despite the importance of metabolic dysfunction-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high-fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single-nucleus RNA sequencing of livers revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female