The aim of this study was to evaluate the effect of a multidisciplinary weight loss intervention on energy intake and appetite sensations in adolescents with obesity, depending on the initial diagnosis or persistence of the metabolic syndrome. Ninety-two adolescents with obesity (12-15 years) followed a 16-week multidisciplinary weight loss intervention. Anthropometric and body composition characteristics, metabolic profile, ad libitum daily energy intake, and appetite sensations were assessed before and after the intervention. The presence of metabolic syndrome (MS) was determined at baseline (MS vs. non-MS) and after the program (persistent vs. non-persistent). While the intervention was effective in inducing weight loss (body weight T0: 87.1 ± 14.9 vs. T1: 81.2 ± 13.0 kg; p < 0.001) and body composition improvements in both adolescents with and without MS, energy intake (p = 0.07), hunger (p = 0.008), and prospective food consumption (p = 0.03) increased, while fullness decreased (p = 0.04) in both groups. Energy intake and appetite were not improved in non-persistent MS after the program and remained significantly higher among non-persistent adolescents compared with initially non-MS adolescents. To conclude, appetite control seems impaired in obese adolescents, irrespective of being affected by MS or not, whereas the treatment of MS in this population might fail to effectively preclude the adolescents from potential post-intervention compensatory food intake and subsequent weight regain.