Adolescents with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) appear to be more likely to experience anxiety and/or depression using Patient Reported Outcome Measures (PROMs). However, we do not know how accurate these are at detecting problems in this patient group given the primary symptom of fatigue. We aimed to accurately determine the prevalence of anxiety/depression using gold-standard diagnostic interviews and evaluate the accuracy of PROMs measuring mood disorders in this patient group. We conducted a cross-sectional epidemiological study in a specialist tertiary paediatric CFS/ME service, England. The participants were164 12–18-year olds with clinician confirmed CFS/ME and their parents. The measures were a semi-structured diagnostic interview, the Kiddie Schedule for Affective Disorders and Schizophrenia, K-SADS, and questionnaires (Revised Children’s Anxiety and Depression Scale, RCADS; Spence Children’s Anxiety Scale, SCAS; Hospital Anxiety and Depression Scale, HADS). Parents completed the RCADS-P. 35% met the criteria for at least one common mental health problem. 20% had major depressive disorder, and 27% an anxiety disorder, with social anxiety and generalised anxiety being the most common. There was high co-morbidity, with 61% of those who were depressed also having at least one anxiety disorder. The questionnaires were moderately accurate (AUC > 0.7) at detecting clinically significant anxiety/depression, although only the RCADS-anxiety reached the predefined 0.8 sensitivity, 0.7 specificity target. Mental health problems are particularly common amongst adolescents with CFS/ME. Most screening tools were not sufficiently accurate in detecting clinically significant anxiety and depression, so these should be used with care in combination with thorough psychological/psychiatric assessment.