Patients who have knee instability that is associated with neuromuscular disease (NMD) and central nervous system (CNS) conditions can be treated using orthoses, such as knee-ankle-foot orthoses (KAFOs). To assess existing evidence on the effectiveness of orthoses; patient perspectives; types of orthotic devices prescribed in the UK NHS; and associated costs. Qualitative study of views of orthoses users - a qualitative in-depth interview study was undertaken. Data were analysed for thematic content. A coding scheme was developed and an inductive approach was used to identify themes. Systematic review - 18 databases were searched up to November 2014: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health, EMBASE, PASCAL, Scopus, Science Citation Index, BIOSIS Previews, Physiotherapy Evidence Database, Recal Legacy, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, Cochrane Central Register of Controlled Trials, Conference Proceedings Citation Index: Science, Health Management Consortium, ClinicalTrials.gov, International Clinical Trials Registry Platform and National Technical Information Service. Studies of adults using an orthosis for instability of the knee related to NMD or a CNS disorder were included. Data were extracted and quality was assessed by two researchers. Narrative synthesis was undertaken. Survey and costing analysis - a web survey of orthotists, physiotherapists and rehabilitation medicine physicians was undertaken. Telephone interviews with orthotists informed a costing analysis. Qualitative study - a total of 24 people participated. Potential for engagement in daily activities was of vital importance to patients; the extent to which their device enabled this was the yardstick by which it was measured. Patients' prime desired outcome was a reduction in pain, falls or trips, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses. Many expressed frustration with perceived deficiencies in service provision relating to appointment and administrative systems and referral pathways. Systematic review - a total of 21 studies (478 participants) were included of people who had post-polio syndrome, inclusion body myositis, were post stroke or had spinal cord injury. The studies evaluated KAFOs (mainly carbon fibre), stance control KAFO and hip KAFOs. All of the studies were at risk of bias and, in general, were poorly reported. Survey and costing analysis - in total, 238 health-care professionals responded. A range of orthoses is prescribed for knee instability that is related to NMD or CNS conditions, approximately half being custom-made. At least 50% of respondents thought that comfort and confidence in mobility were extremely important treatment outcomes. The cost of individual KAFOs was highly variable, ranging from £73 to £3553. Various types of orthoses are used in the NHS to manage patients with NMD/CNS conditions and knee instability, both custom-made and prefabricated, of variable cost. Evidence on the effectiveness of the orthoses is limited, especially in relation to the outcomes that are important to orthoses users. The population included was broad, limiting any in-depth consideration of specific conditions. The response rate to the survey was low, and the costing analysis was based on some assumptions that may not reflect the true costs of providing KAFOs. Future work should include high-quality research on the effectiveness and cost-effectiveness of orthoses; development of a core set of outcome measures; further exploration of the views and experiences of patients; and the best models of service delivery. This study is registered as PROSPERO CRD42014010180. The qualitative study is registered as Current Controlled Trials ISRCTN65240228. The National Institute for Health Research Health Technology Assessment programme.