We examined the effects of a 10–14-weeks inpatient lifestyle modification program, including minimum 90 min of physical activity (PA) five days/week, on body composition, CVD risk factors, and eating behavior in 139 obese subjects (BMI 42.6 ± 5.2 kg/m2). Completion rate was 71% (n = 71) in the intensive lifestyle intervention (ILI) group and 85% (n = 33) among waiting list controls. Compared to controls body weight (−17.0 (95% CI: −18.7, −15.3) kg, P < 0.0001), fat mass (−15.2 (95% CI: −17.4, −13.1) kg, P < 0.0001), fat free mass (−1.2 (95% CI: −2.2, −0.2) kg, P = 0.016) and visceral fat (−86.6(95% CI: −97.4, −75.7) cm2, P < 0.0001) were reduced in the ILI-group after 10–14 weeks. Within the ILI-group weight loss was −23.8 (95% CI: −25.9, −21.7) kg, P < 0.0001 and -20.3 (95% CI: −23.3, −17.3) kg, P < 0.0001, after six and 12 months, respectively. Systolic BP, glucose, triglycerides, and LDL-C were reduced, and HDL-C was increased (all P ≤ 0.006) after 10–14 weeks within the ILI group. The reduction in glucose and increase in HDL-C were sustained after 12 months (all P < 0.0001). After one year, weight loss was related to increased cognitive restraint and decreased uncontrolled eating (all P < 0.05). Thus, ILI including high volume of PA resulted in weight loss with almost maintenance of fat-free mass, favorable changes in CVD risk factors, and eating behavior in subjects with severe obesity.