1. Stress is associated with a severe, yet reversible, form of insulin resistance. The aim of this study was to quantify the kinetics of insulin action (sensitivity and responsiveness) on intermediary metabolism during post-surgical stress. 2. We studied nine patients 6-8 h after major uncomplicated surgery, and eight healthy subjects matched for age, weight, glucose tolerance and duration of fast. A three-step isoglycaemic insulin clamp was combined with indirect calorimetry, [6-3H]glucose infusion and the forearm technique. 3. The following significant (P < 0.05 or less) abnormalities were found in the patients. Hepatic glucose production was higher at baseline, and less suppressed by insulin. Whole-body glucose disposal was impaired at all insulin doses (by 33-60%). Glucose oxidation was depressed throughout the dose range but its increments in response to insulin were normal. In contrast, non-oxidative glucose disposal was essentially unresponsive. At all insulin levels, forearm glucose extraction was markedly depressed and forearm lactate release was in excess of concurrent glucose uptake, suggesting ongoing glycogenolysis despite insulin. Total lipolysis (plasma free fatty acid and glycerol levels) promptly responded to insulin but remained higher than in the control subjects throughout. In the forearm, even the highest insulin dose could not suppress net free fatty acid and glycerol release. Total lipid oxidation was increased throughout the insulin range, and calculated direct free fatty acid (as opposed to plasma free fatty acid) oxidation was virtually unaffected by insulin. Protein oxidation was slightly (35%) increased, but was suppressed normally in response to insulin. Energy expenditure was 20% higher at baseline, and failed to rise with insulin. Arterial blood pH values were consistently (if slightly) lower, and net forearm proton release was higher, both at baseline and during insulin infusion. 4. Post-surgical insulin resistance is characterized by normal sensitivity but decreased responsiveness of glucose oxidation, lipolysis and plasma free fatty acid oxidation, whereas glycogen synthesis and direct free fatty acid oxidation are virtually unresponsive. For both glucose and lipid metabolism, the insulin resistance is particularly severe in forearm tissues, in which mild metabolic acidosis may play an additional role.