BACKGROUND: The impact of the dietary macronutrient composition and its subcomponents (saccharides, fatty acids, and protein sources) on radiation-induced acute skin toxicity (AST) in breast cancer (BC) patients is unknown. Hence, we examined the association between dietary macronutrients and their subcomponents and the risk of ≥grade 2 (G2) AST post-radiotherapy among women with BC. METHODS: An observational study was conducted among 161 BC patients treated with radiotherapy and enrolled in the ATHENA project in Italy. Habitual dietary intake was assessed at study entry (T0) using a 188-item food frequency questionnaire (FFQ). AST was measured at T1 (after 3 or 5 weeks of radiotherapy) and defined according to the Radiation Therapy Oncology Group criteria. A prospective analysis used multivariable-adjusted logistic regression models to examine the association between the dietary macronutrient composition and its subcomponents at T0 and the odds of ≥G2 AST post-radiotherapy. RESULTS: ≥G2 AST post-radiotherapy was observed in 43 (27%) patients. Among dietary macronutrient models, a higher intake of dietary carbohydrates was positively associated with a 30% higher odds of ≥G2 AST post-radiotherapy (OR = 1.30; 95% CI 1.01 to 1.67; for 30 g/d). Conversely, a higher dietary protein intake was inversely associated with a 76% lower odds of ≥G2 AST post-radiotherapy (OR = 0.24; 95% CI 0.06 to 0.91; for 30 g/d). There was no association with dietary fat. In macronutrient subcomponent models, only animal protein was inversely associated with a 51% lower odds of ≥G2 AST post-radiotherapy (0.49; 95% CI 0.25 to 0.95; for 15 g/d). CONCLUSIONS: Dietary carbohydrates were associated with a higher risk of radiation-induced AST among women with BC, whereas dietary protein, especially animal protein, was associated with a lower risk. Cautiously balancing carbohydrate and protein intakes could be a part of the clinical management strategy for ≥G2 AST reduction post-radiotherapy among BC women.