Few short-term studies of weight loss have been performed in adult patients with Prader-Willi syndrome (PWS) undergoing metabolic rehabilitation. We performed a retrospective cohort study of 45 adult obese PWS patients undergoing a long-term multidisciplinary metabolic rehabilitation program based on diet and physical activity. Body composition was evaluated by dual-energy X-ray absorptiometry in 36 (80%) patients. The mean (95% CI) weight change was -3.6 (-7.6 to 0.4, p = 0.08) kg at 3 years and -4.6 (-8.5 to -0.8, p = 0.02) kg at 6 years, and that of BMI was -1.7 (-3.4 to 0.1, p = 0.06) kg/m2 at 3 years and -2.1 (-3.8 to -0.4, p = 0.02) kg/m2 at 6 years. A decrease of about 2% in fat mass per unit of body mass was observed, which is in line with the expectations for moderate weight loss. A possibly clinically relevant decrease in total and low-density lipoprotein cholesterol was also observed. These long-term results are important for patients with PWS, which is characterized by severe hyperphagia, behavioral disturbances, and cognitive impairment and is generally considered "resistant" to classical weight loss interventions.