(1) Background: Chronic musculoskeletal pain (CMP) in adolescents can negatively affect physical, psychological and social functioning, resulting in functional disability. This study aims to evaluate the effectiveness of an outpatient rehabilitation program based on graded exposure in vivo (EP) compared with care as usual (CAU) in a RCT. The aim of the interventions (EP and CAU) is to improve functional ability in adolescents with CMP, CAU is interdisciplinary outpatient rehabilitation care, based on graded activity. (2) Methods: A pragmatic multicenter randomized clinical trial with a 12-month follow-up was used. Adolescents (12-21 years) with musculoskeletal pain were invited to participate. Primary outcome was functional disability (Functional Disability Inventory). Most important secondary measures: perceived harmfulness, pain catastrophizing and intensity. Data analysis was performed by intention-to-treat linear mixed model analysis. (3) Results: Sixty adolescents were randomized to EP or CAU and data of 53 adolescents (93% female) could be analyzed (25 EP, 28 CAU). Mean age was 16.0 years (SD=1.87). Adolescents in EP showed a clinically relevant and statistically significant decrease in functional disability (estimated mean difference at least -8.81,p-values≤0.01) compared with CAU at all time points. Significant differences in favor of EP were found for perceived harmfulness at all time points (p-values≤0.002), for pain catastrophizing (PCS) at 2 months follow-up (p-value=0.039) and for pain intensity at 4 and 10 months follow-up (p-values≤0.028). (4) Conclusion: The effectiveness of the trial is in favor of the EP and leads to a significant and clinically relevant decrease in functional disability compared to usual care.