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Background: First contact physiotherapy practitioners (FCPPs) are embedded within general practice, providing expert assessment, diagnosis, and management plans for patients with musculoskeletal disorders (MSKDs), without the prior need for GP consultation. Aim: To determine the clinical effectiveness and costs of FCPP models compared with GP-led models of care. Design and setting: Multiple site case-study design of general practices in the UK. Method: General practice sites were recruited representing the following three models: 1) GP-led care; 2) FCPPs who could not prescribe or inject (FCPPs-standard [St]); and 3) FCPPs who could prescribe and/or inject (FCPPs-additional qualifications [AQ]). Patient participants from each site completed outcome data at baseline, 3 months, and 6 months. The primary outcome was the SF-36 Physical Component Summary (PCS) score. Healthcare usage was collected for 6 months. Results: In total, 426 adults were recruited from 46 practices across the UK. Non-inferiority analysis showed no significant difference in physical function (SF-36 PCS) across all three arms at 6 months (P = 0.667). At 3 months, a significant difference in numbers improving was seen between arms: 54.7% (n = 47) GP consultees, 72.4% (n = 71) FCPP-St, and 66.4% (n = 101) FCPP-AQ (P = 0.037). No safety issues were identified. Following initial consultation, a greater proportion of patients received medication (including opioids) in the GP-led arm (44.7%, n = 42), compared with FCPP-St (18.4%, n = 21) and FCPP-AQ (24.7%, n = 40) (P<0.001). NHS costs (initial consultation and over 6-month follow-up) were significantly higher in the GP-led model (median £105.5 per patient) versus FCPP-St (£41.0 per patient) and FCPP-AQ (£44.0 per patient) (P<0.001). Conclusion: FCPP-led models of care provide safe, clinically effective patient management, with cost-benefits and reduced opioid use in this cohort. [ABSTRACT FROM AUTHOR]