Abstract Background Low back pain (LBP) is the leading cause of disability worldwide, presenting a substantial societal burden. This calls for the optimization of care pathways to enhance the efficacy of the management of LBP. Physiotherapists (PT), who have unique expertise in movement and the musculoskeletal system, can adopt a central role in the primary care for LBP. International research has shown that PT-led care for musculoskeletal conditions improved clinical efficacy, reduced waiting times, resulted in higher satisfaction among patients and referrers, and was not associated with increased harm. However, PT-led care still needs to be explored in Belgium despite its acceptance in 72% of World Confederation for Physical Therapy (WCPT) member countries, encompassing various European nations. Purpose The primary objective is to examine the clinical efficacy of PT-led care compared to General Practitioner (GP)-led care for patients with acute LBP in Belgium. The secondary objective is to identify which patients’ biopsychosocial factors determine the clinical efficacy of PT-led care. Methods In a quasi-randomized controlled trial, 640 subjects with acute LBP will receive PT-led care or GP-led care. Demographics and risk of chronicity (Start Back Tool [SBT]) will be assessed at baseline. LBP-related disability (Oswestry Disability Index [ODI]), pain intensity (Numeric Pain Rating Scale [NRS]) and pain extent (Pain Drawing) will be evaluated at baseline, every week from the first to the sixth week and at three months, six months, one year and two years. Attitudes and beliefs (Fear-Avoidance Beliefs Questionnaire [FABQ] and Back Pain Attitudes Questionnaire [Back-PAQ]) and self-efficacy (General Self-Efficacy Scale [GSES]) will be assessed at baseline, three months, six months, one year and two years. Baseline group characteristics will be displayed using descriptive statistics. Based on a data normality check, parametric or non-parametric statistics will be performed and the significance level of α=0.05 will be ...