A single bout of moderate-intensity exercise increases whole-body insulin sensitivity for 12-48 h post-exercise; however, the relationship between exercise energy expenditure and the improvement in insulin sensitivity is not known. We hypothesized that the exercise-induced increase in whole-body insulin sensitivity, assessed with HOMA_IR (homoeostasis model assessment of insulin resistance), is directly related to the energy expended during exercise. We studied 30 recreationally active non-obese men (age, 27+/-5 years; body mass index, 24+/-2 kg/m²) in the post-absorptive state on two separate occasions: once after exercising at 60% of VO_22peak (peak oxygen consumption) for 30-120 min on the preceding afternoon (expending a total of 1.28-5.76 MJ) and once after an equivalent period of rest. Blood samples were obtained the following morning. Exercise-induced changes in HOMA_IR were curvilinearly related to exercise energy expenditure (r=-0.666, P=0.001) with a threshold of approx. 3.77 MJ (900 kcal) for improvements in HOMA_IR to be manifested. In particular, HOMA_IR was reduced by 32+/-24% (P=0.003) in subjects who expended more than 3.77 MJ during exercise, but did not change for those who expended fewer than 3.77 MJ (-2+/-21%; P=0.301). Furthermore, the magnitude of change in HOMA_IR after exercise was directly associated with baseline (i.e. resting) HOMA_IR (r=-0.508, P=0.004); this relationship persisted in multivariate analysis. We conclude that improved whole-body insulin resistance after a single bout of exercise is curvilinearly related to exercise energy expenditure, and requires unfeasible amounts of exercise for most sedentary individuals.