Objectives: To determine the effectiveness of early multidisciplinary interventions in promoting work participation and reducing work absence in adults with regional musculoskeletal pain. Data sources: Seven databases (CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, OT Seeker, PEDro; 1990 to December 2016) were searched for eligible studies. Review methods: Trials were included if they reported on work-based outcomes for participants experiencing difficulties at work or ≤ three months’ sick leave. Interventions had to include two or more elements of the biopsychosocial model delivered as a coordinated programme. Quality was assessed using the GRADE criteria. Results were analysed by hazard ratios for return to work data; continuous outcomes were analysed as standardised mean difference with 95% confidence intervals. Results: A total of 20 randomized controlled trials, with 16,319 participants were included; the interventions were grouped according to their main components for meta-analyses. At 12-months follow-up, moderate quality evidence suggests that programmes involving a stepped care approach (four studies) were more effective than the comparisons in promoting return to work (hazard ratio (HR) 1.29 (95% confidence interval (CI) 1.03 to 1.61), p = 0.03), whereas case management (two studies) was not (HR 0.92 (95% CI 0.69 to 1.24), p = 0.59). Analyses suggested limited effectiveness in reducing sickness absences, in pain reduction or functional improvement across the intervention categories. Conclusion: There is uncertainty as to the effectiveness of early multicomponent interventions owing to the clinical heterogeneity and varying health and social insurance systems across the trials.