To determine whether a fast reduction in fat mass can be achieved in 4 days by combining caloric restriction (CR: 3.2kcal/kg body weight per day) with exercise (8-h walking+45-min arm cranking per day) to induce an energy deficit of approximate to 5000kcal/day, 15 overweight men underwent five experimental phases: pretest, exercise+CR for 4 days (WCR), control diet+reduced exercise for 3 days (DIET), and follow-up 4 weeks (POST1) and 1 year later (POST2). During WCR, the diet consisted solely of whey protein (n=8) or sucrose (n=7) (0.8g/kg body weight per day). After WCR, DIET, POST1, and POST2, fat mass was reduced by a mean of 2.1, 2.8, 3.8, and 1.9kg (P<0.05), with two thirds of this loss from the trunk; and lean mass by 2.8, 1.0, 0.5, and 0.4kg, respectively. After WCR, serum glucose, insulin, homeostatic model assessment, total and low-density lipoprotein cholesterol and triglycerides were reduced, and free fatty acid and cortisol increased. Serum leptin was reduced by 64%, 50%, and 33% following WCR, DIET, and POST1, respectively (P<0.05). The effects were similar in both groups. In conclusion, a clinically relevant reduction in fat mass can be achieved in overweight men in just 4 days by combining prolonged exercise with CR.