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Introduction: Knee pain is common in adolescents and adults and is associated with an increased risk of developing knee osteoarthritis. The aim of this systematic review was to gather and appraise the cost-effectiveness of treatment approaches for non-osteoarthritic knee pain conditions. Method: A systematic review was conducted according to the PRISMA guidelines and registered on PROSPERO (CRD42016050683). The literature search was done in MEDLINE via PubMed, EMBASE, The Cochrane Library, and the National Health Service Economic Evaluation Database. Study selection was carried out by two independent reviewers and data were extracted using a customized extraction form. Study quality was assessed using the Consensus on Health Economic Criteria list. Results: Fifteen studies were included. The majority regarded the treatment of anterior cruciate ligament (ACL) injuries, but we also identified studies evaluating other knee pain conditions such as meniscus injuries, cartilage defects, and patellofemoral pain syndrome. Study interventions were categorized as surgical or non-surgical interventions. The surgical interventions included ACL reconstruction, chondrocyte implantation, meniscus scaffold procedure, meniscal allograft transplantation, partial meniscectomy, microfracture, and different types of autografts and allografts. The non-surgical management consisted of physical therapy, rehabilitation, exercise, counselling, bracing, and advice. In general, for ACL injuries surgical management alone or in combination with rehabilitation appeared to be cost-effective. The quality of the economic evaluations was of moderate to high quality. Conclusion: There was insufficient evidence to give a firm overview of cost-effective interventions for non-osteoarthritic knee pain, but surgical treatment of acute ACL injury appeared cost-effective. There is very little data regarding the cost-effectiveness of non-surgical interventions for non-traumatic knee conditions. [ABSTRACT FROM AUTHOR]