We investigated which determinants (socioeconomic, early life factors, body composition changes, fitness changes and/or physical activity changes) best predicted longitudinal outcomes in cardiometabolic risk profile (Z-score change) in adolescents with OW/OB who underwent a 13-month multidisciplinary lifestyle intervention. A total of 165 adolescents (13–16 y; 46% boys) from the EVASYON study were included. Socioeconomic variables and early life factors were obtained from the medical records. Body composition was assessed using anthropometry. Fitness and physical activity were measured with field-based tests and questionnaires. Cardiometabolic risk factors (fasting glucose, HDL cholesterol, triglycerides, blood pressure and waist circumference) were derived from standard methods in the hospital. Body weight changes, sex and mother’s education were selected in the stepwise process as the most important determinants of changes in cardiometabolic risk profile (R2 = 0.26, p = 0.002; R2 = 0.14, p = 0.013; and R2 = 0.14, p = 0.017, respectively). Both boys and girls showed a lower cardiometabolic risk score with the reduction in body weight (r = 0.535, p = 0.009 and r = 0.506, p = 0.005, respectively). There was no interaction between sex and body weight change (p = 0.614). In conclusion, the simple measure of changes in body weight should be considered to track changes in cardiometabolic risk profile in adolescents with OW/OB.