Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work inDrosophilashowed that body size plasticity was higher in females, yet the mechanisms underlying the sex difference in body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-specific increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This increased IIS activity was triggered by a diet-induced increase instunted, and requiredDrosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination genetransformerregulates the diet-induced increase instuntedand IIS activity, and mediates the sex difference in body size plasticity. This identifies one sex-specific mechanism underlying the nutrient-dependent regulation of IIS activity and body size plasticity, providing vital insight into conserved mechanisms that mediate sex differences in phenotypic plasticity.