Intermittent fasting (IF) is a beneficial dietary treatment for obesity that improves liver health. A major co-morbidity of obesity is non-alcoholic fatty liver disease (NAFLD), where the accumulation of liver fat leads to fibrosis and reduced liver function. The risk for NAFLD is higher in men and post-menopausal women, which suggests sex hormones play a critical role in NAFLD prevention. Recently, we completed the first proteomic analysis of IF in both male and female mice. Of the 4500 proteins identified, 1050 were significant for IF-responsiveness, 800 were enriched in one sex and 500 were differently regulated by IF between the sexes. This strongly supports a sexually dimorphic response to IF in the liver. Strikingly, females had vastly increased interferon-alpha (IFNα) pathway induction after IF, whereas males had very little induction. To determine if ongoing sex hormone action was required for these differences, we applied IF to either castrated or sham treated mice. In the absence of testosterone, IFNα signaling increased in the liver after IF which suggests the androgen receptor actively suppresses IFNα pathway induction. Currently, we are performing similar experiments in ovariectomised mice to dissect the role of estrogen in the IF response. IFNα signaling has previously been shown to reduce lipid accumulation and fibrosis within the liver. Further questions remain about the protective efficacy of IF for liver fibrosis, which we aim to test in a mouse NAFLD/fibrosis model. This works highlights an interesting link between IF and sex with potential consequences for human treatment and disease prevention. Identification of pathways triggering the IF response could lead to therapeutic strategies to treat liver disease.