AbstractBackgroundEvidence for treatment of adolescents with multiple functional somatic syndromes (FSS) is sparse. This study examined the efficacy of ‘Acceptance and Commitment Therapy for Health in Adolescents’ (AHEAD), a generic group‐based treatment for adolescents with co‐occurrence of multiple FSS.MethodsA randomized trial was conducted at a specialized university hospital clinic. Adolescents (15–19 years) with multiple FSS of at least 1 year's duration were randomly assigned to AHEAD or enhanced usual care (EUC). AHEAD consisted of nine modules (i.e., 27 h) and one follow‐up meeting. Primary outcome was physical health (SF‐36). Various secondary outcomes and treatment targets were included (e.g., symptom severity, symptom impact, and illness perception). A linear mixed‐effects model was used for analysis. Trial‐registration:ClinicalTrials.govNCT02346071.ResultsNinety‐one patients were included. At 12 months, no significant difference in physical health was identified between groups (mean adjusted difference 1.2 [95% CI −1.6 to 4.0],p= .404). However, different developments over time were seen with an interaction effect between intervention arm and time (χ2(5) = 14.1,p= .0148). AHEAD patients (n= 44) reported a clinically relevant improvement at end of treatment and at 8 and 12 months, while EUC patients (n= 47) displayed a clinically relevant improvement at 12 months. Furthermore, AHEAD patients showed a faster improvement on symptom severity, symptom impact and illness perception. EUC patients received more psychological treatment outside the trial (p≤ .001) than AHEAD patients. Treatment satisfaction with AHEAD was high in contrast to EUC.ConclusionsCompared with EUC, AHEAD had no additional advantage on the improvement of physical health at the primary endpoint of 12 months. However, a faster improvement of physical health was seen in AHEAD and considerably more psychological treatment was received outside the trial in EUC with clinically meaningful improvements in both groups. The results underpin the importance of an organised and systematic treatment offer for the most severely affected youth.