BACKGROUND: Low back pain (LBP) is a multifactorial condition with individual and societal impact that affects populations globally. Current guidelines for the treatment of LBP recommend pharmacological and non-pharmacological strategies. The aim of this study was to compare usual clinical practice with the effectiveness of a biopsychosocial multidisciplinary intervention in reducing disability, severity of pain and improving quality of life in a working population of patients with subacute (2-12 weeks), non-specific LBP. METHODS: Longitudinal cluster randomized clinical trial conducted in 39 Primary Health Care Centres (PHCC) of Barcelona, with patients aged 18-65 years (n = 501; control group = 239; 26 PHCC, intervention group = 262; 13 PHCC). The control group received usual clinical care. The intervention group received usual clinical care plus a biopsychosocial multidisciplinary intervention, which consisted of physiotherapy, cognitive-behavioural therapy and medication. The main outcomes were changes in the Roland Morris Disability Questionnaire (RMDQ), and the minimal clinically important differences. Secondary outcomes were changes in the McGill Pain (MGPQ) and Quality of Life (SF-12) questionnaires. Assessment was conducted at baseline, 3 and 12 months. Analysis was by intention-to-treat and analyst-blinded. Multiple imputations were used. RESULTS: Of the 501 enrolled patients, 421 (84%) provided data at 3 months, and 387 (77.2%) at 12 months. Mean age was 46.8 years (SD: 11.5) and 64.7% were women. In the adjusted analysis of the RMDQ outcome, only the intervention group showed significant changes at 3 months (- 1.33 points, p = 0.005) and at 12 months (- 1.11 points, p = 0.027), but minimal clinically important difference were detected in both groups. In the adjusted analysis of the RMDQ outcome, the intervention group improvement more than the control group at 3 months (- 1.33 points, p = 0.005) and at 12 months (- 1.11 points, p = 0.027). The intervention group presented a significant difference. Both groups presented a minimal clinically important difference, but more difference in the intervention group. The intervention group presented significant differences in the MGPQ scales of current pain intensity and VAS scores at 3 months. No statistically significant differences were found in the physical and mental domains of the SF-12. CONCLUSIONS: A multidisciplinary biopsychosocial intervention in a working population with non-specific subacute LBP has a small positive impact on disability, and on the level of pain, mainly at short-term, but no difference on quality of life. TRIAL REGISTRATION: ISRCTN21392091 (17 oct 2018) (Prospectively registred)