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Background: Muscle atrophy, muscle weakness and localised pain are commonly reported following musculoskeletal injury (MSKI). To mitigate this risk and prepare individuals to return to sport or physically demanding occupations, resistance training (RT) is considered a vital component of rehabilitation. However, to elicit adaptations in muscle strength, exercise guidelines recommend lifting loads ≥ 70% of an individual's one repetition maximum (1-RM). Unfortunately, individuals with persistent knee pain are often unable to tolerate such high loads and this may negatively impact the duration and extent of their recovery. Low load blood flow restriction (LL-BFR) is an alternative RT technique that has demonstrated improvements in muscle strength, hypertrophy, and pain in the absence of high mechanical loading. However, the effectiveness of high-frequency LL-BFR in a residential rehabilitation environment remains unclear. This study will compare the efficacy of high frequency LL-BFR to 'conventional' heavier load resistance training (HL-RT) on measures of physical function and pain in adults with persistent knee pain., Methods: This is a multicentre randomised controlled trial (RCT) of 150 UK service personnel (aged 18-55) admitted for a 3-week residential rehabilitation course with persistent knee pain. Participants will be randomised to receive: a) LL-BFR delivered twice daily at 20% 1-RM or b) HL-RT three-times per week at 70% 1-RM. Outcomes will be recorded at baseline (T1), course discharge (T2) and at three-months following course (T3). The primary outcome will be the lower extremity functional scale (LEFS) at T2. Secondary outcomes will include patient reported perceptions of pain, physical and occupational function and objective measures of muscle strength and neuromuscular performance. Additional biomechanical and physiological mechanisms underpinning both RT interventions will also be investigated as part of a nested mechanistic study., Discussion: LL-BFR is a rehabilitation modality that has the potential to induce positive clinical adaptations in the absence of high mechanical loads and therefore could be considered a treatment option for patients suffering significant functional deficits who are unable to tolerate heavy load RT. Consequently, results from this study will have a direct clinical application to healthcare service providers and patients involved in the rehabilitation of physically active adults suffering MSKI., Trial Registration: ClinicalTrials.org reference number, NCT05719922., (© 2023. Crown.)