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Although several studies have illustrated the effectiveness of cognitive behavior therapy (CBT) on adult pain patients, there are few randomized controlled trials on children and adolescents. There is particularly a need for studies on pediatric patients who are severely disabled by longstanding pain syndromes. Acceptance and Commitment Therapy, as an extension of traditional CBT, focuses on improving functioning and quality of life by increasing the patient’s ability to act effectively in concordance with personal values also in the presence of pain and distress. Following a pilot study, we sought to evaluate the effectiveness of an ACT-oriented intervention based on exposure and acceptance strategies and to compare this with a multidisciplinary treatment approach including amitriptyline (n = 32). The ACT condition underwent a relatively brief treatment protocol of approximately 10 weekly sessions. Assessments were made before and immediately after treatment, as well as at 3.5 and 6.5 months follow-up. Prolonged treatment in the MDT group complicated comparisons between groups at follow-up assessments. Results showed substantial and sustained improvements for the ACT group. When follow-up assessments were included, ACT performed significantly better than MDT on perceived functional ability in relation to pain, pain intensity and to pain-related discomfort (intent-to-treat analyses). At post-treatment, significant differences in favor of the ACT condition were also seen in fear of re/injury or kinesiophobia, pain interference and in quality of life. Thus, results from the present study support previous findings and suggest the effectiveness of this ACT-oriented intervention for pediatric longstanding pain syndromes.