In natural environments animals normally experience periods of feast and famine due to the intermittent availability of food. Indeed, intermittent fasting (IF) provides beneficial effects relative to providing constant access to food, which shortens lifespan and produces undesirable metabolic outcomes. Strikingly, all previous molecular studies of the response to intermittent food availability have exclusively analysed male animals. However, it is axiomatic that males and females differ in many aspects of their physiology, and their response to intermittent feeding/starvation is no exception. For example, in humans females live longer, have more lipid-based energy reserves, and are more resistant to infection compared to males. Global mRNA studies in mice have also shown many genes are expressed in a sexually dimorphic pattern including those in the liver, a key nutrient-responsive organ. Here, we have employed proteome analysis of mouse liver to identify proteins whose abundance is regulated by IF, but are also sexually dimorphic in their response. From >6,800 proteins quantified, 663 proteins were significantly altered by the IF intervention. Of these IF-responsive proteins, 171 had a significant interaction with the gender of the animals indicating sexual dimorphism. Proteins showing the largest interaction included IFIT1 (innate immune response), ACOT2, (fatty acid degradation), SERPINA1 (major secreted protease inhibitor), and SELENBP1 (organosulfur degradation). Gene-set enrichment analysis showed that the interferon-alpha pathway was a major contributor to the sexual dimorphism with the transcription factor STAT1 being the likely master regulator of this response. These data correlate with the known differences in immune response between genders, where female liver is less likely to become infected by viral pathogens due to heightened interferon signaling. But how the gender difference in interferon signaling is generated for non-infected animals exposed to intermittent fasting is unknown. We hypothesise that the large flux in free fatty acids produced during intermittent fasting can lead to activation of STAT1 and thereby the entire downstream interferon responsive machinery, which we are currently testing by exogenous injection experiments across genders.