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Research has shown that mindfulness-based treatment interventions may be effective for a range of mental and physical health disorders in adult populations, but little is known about the effectiveness of such interventions for treating adolescent conditions. The present randomized clinical trial was designed to assess the effect of the mindfulness-based stress reduction (MBSR) program for adolescents age 14 to 18 years with heterogeneous diagnoses in an outpatient psychiatric facility (intent-to-treat N = 102). Relative to treatment-as-usual control participants, those receiving MBSR self-reported reduced symptoms of anxiety, depression, and somatic distress, and increased self-esteem and sleep quality. Of clinical significance, the MBSR group showed a higher percentage of diagnostic improvement over the 5-month study period and significant increases in global assessment of functioning scores relative to controls, as rated by condition-naïve clinicians. These results were found in both completer and intent-to-treat samples. The findings provide evidence that MBSR may be a beneficial adjunct to outpatient mental health treatment for adolescents.