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Pharmacological interventions are essential for the treatment and management of critical illness. Although women comprise a large proportion of the critically ill, sex-specific pharmacological properties are poorly described in critical care. The sex-specific effects of vitamin D₃ treatment in the critically ill are not known. Therefore, we performed a metabolomics cohort study with 1215 plasma samples from 428 patients from the VITdAL-ICU trial to study sex-specific differences in the metabolic response to critical illness following high-dose oral vitamin D₃ intervention. In women, despite the dose of vitamin D₃ being higher, pharmacokinetics demonstrated a lower extent of vitamin D₃ absorption compared to men. Metabolic response to high-dose oral vitamin D₃ is sex-specific. Sex-stratified individual metabolite associations with elevations in 25(OH)D following intervention showed female-specific positive associations in long-chain acylcarnitines and male-specific positive associations in free fatty acids. In subjects who responded to vitamin D₃ intervention, significant negative associations were observed in short-chain acylcarnitines and branched chain amino acid metabolites in women as compared to men. Acylcarnitines and branched chain amino acids are reflective of fatty acid B oxidation, and bioenergesis may represent notable metabolic signatures of the sex-specific response to vitamin D. Demonstrating sex-specific pharmacometabolomics differences following intervention is an important movement towards the understanding of personalized medicine. Full article