More complex surgeries are being performed in increasingly sicker patients, resulting in a greater burden of postoperative morbidity. Delineating the metabolic and bioenergetic changes that occur in response to surgical stress may further our understanding about how humans respond to injury and aid the identification of resilient and frail phenotypes. Skeletal muscle biopsies were taken from patients undergoing hepato-pancreatico-biliary surgery at the beginning and end of the procedure to measure mitochondrial respiration and thiol status. Blood samples were taken at the same timepoints to measure markers of inflammation and systemic redox state. A sub-group of patients underwent cardiopulmonary exercise testing prior to surgery, and were assigned to two groups according to their oxygen consumption at anaerobic threshold (≤10 and >
10 mL/kg/min) to determine whether redox phenotype was related to cardiorespiratory fitness. No change in mitochondrial oxidative phosphorylation capacity was detected. However, a 26.7% increase in LEAK (uncoupled) respiration was seen after surgery (P = 0.03). Free skeletal muscle cysteine also increased 27.0% (P = 0.003), while S-glutathionylation and other sulfur and nitrogen-based metabolite concentrations remained unchanged. The increase in LEAK was 200% greater in fit patients (P = 0.004). Baseline plasma inflammatory markers, including TNF-⍺ and IL-6 were greater in unfit patients, 96.6% (P = 0.04) and 111.0% (P = 0.02) respectively, with a 58.7% lower skeletal muscle nitrite compared to fit patients. These data suggest that oxidative phosphorylation is preserved during the acute intraoperative period. Increase in free cysteine may demonstrate the muscle's response to surgical stress to maintain redox balance. The differences in tissue metabolism between fitness groups suggests underlying metabolic phenotypes of frail and resilient patients. For example, increased LEAK in fitter patients may indicate mitochondrial adaptation to stress. Higher baseline measurements of inflammation and lower tissue nitrite in unfit patients, may reflect a state of frailty and susceptibility to postoperative demise.