BackgroundAlthough mental health difficulties can severely complicate the lives of children and young people (CYP) with long-term physical conditions (LTCs), there is a lack of evidence about the effectiveness of interventions to treat them.ObjectivesTo evaluate the clinical effectiveness and cost-effectiveness of interventions aiming to improve the mental health of CYP with LTCs (review 1) and explore the factors that may enhance or limit their delivery (review 2).Data sourcesFor review 1, 13 electronic databases were searched, including MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Science Citation Index. For review 2, MEDLINE, PsycINFO and CINAHL were searched. Supplementary searches, author contact and grey literature searches were also conducted.Review methodsThe first systematic review sought randomised controlled trials (RCTs) and economic evaluations of interventions to improve elevated symptoms of mental ill health in CYP with LTCs. Effect sizes for each outcome were calculated post intervention (Cohen’sd). When appropriate, random-effects meta-analyses produced pooled effect sizes (d). Review 2 located primary qualitative studies exploring experiences of CYP with LTCs, their families and/or practitioners, regarding interventions aiming to improve the mental health and well-being of CYP with LTCs. Synthesis followed the principles of metaethnography. An overarching synthesis integrated the findings from review 1 and review 2 using a deductive approach. End-user involvement, including topic experts and CYP with LTCs and their parents, was a feature throughout the project.ResultsReview 1 synthesised 25 RCTs evaluating 11 types of intervention, sampling 12 different LTCs. Tentative evidence from seven studies suggests that cognitive–behavioural therapy interventions could improve the mental health of CYP with certain LTCs. Intervention–LTC dyads were diverse, with few opportunities to meta-analyse. No economic evaluations were located. Review 2 synthesised 57 studies evaluating 21 types of intervention. Most studies were of individuals with cancer, a human immunodeficiency virus (HIV) infection or mixed LTCs. Interventions often aimed to improve broader mental health and well-being, rather than symptoms of mental health disorder. The metaethnography identified five main constructs, described in an explanatory line of argument model of the experience of interventions. Nine overarching synthesis categories emerged from the integrated evidence, raising implications for future research.LimitationsReview 1 conclusions were limited by the lack of evidence about intervention effectiveness. No relevant economic evaluations were located. There were no UK studies included in review 1, limiting the applicability of findings. The mental health status of participants in review 2 was usually unknown, limiting comparability with review 1. The different evidence identified by the two systematic reviews challenged the overarching synthesis.ConclusionsThere is a relatively small amount of comparable evidence for the effectiveness of interventions for the mental health of CYP with LTCs. Qualitative evidence provided insight into the experiences that intervention deliverers and recipients valued. Future research should evaluate potentially effective intervention components in high-quality RCTs integrating process evaluations. End-user involvement enriched the project.Study registrationThis study is registered as PROSPERO CRD42011001716.FundingThe National Institute for Health Research (NIHR) Health Technology Assessment programme and the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.