BACKGROUND: Musculoskeletal pain (MSP) is the leading cause of years lived with disability. In consequence, to reduce MSP and its associated sickness absence is a major challenge. Previous interventions have been developed to reduce MSP and improve return to work of workers with MSP, but combined approaches and exhaustive evaluation are needed. The objective of the INTEVAL_Spain project is to evaluate the effectiveness of a multifaceted intervention in the workplace to prevent and manage MSP in nursing staff. METHODS: The study is designed as a two-armed cluster randomized controlled trial with a late intervention control group. The hospital units are the clusters of randomization and participants are nurses and aides. An evidence-based multi-component intervention was designed combining participatory ergonomics, case management and health promotion. Both the intervention and the control groups receive occupational health care as usual. Data are collected at baseline, and after six and 12 months. The primary outcomes are prevalence of MSP and incidence and duration of sickness absence due to MSP. Secondary outcomes are work role functioning and organizational preventive culture. The intervention process will be assessed through quantitative indicators of recruitment, context, reach, dose supplied, dose received, fidelity and satisfaction, and qualitative approaches including discussion groups of participants and experts. The economic evaluation will include cost-effectiveness and cost-utility, calculated from the societal and the National Health System perspectives. DISCUSSION: Workplace health programs are one of the best options for the prevention and control of non-communicable diseases. The main feature of this study is its multifaceted, multidisciplinary and de-medicalized intervention, which encompasses three evidence-based interventions and covers all three levels of prevention, which have not been previously unified in a single intervention. Also, it includes a comprehensive quantitative and qualitative evaluation of the intervention process, health results, and economic impact. This study could open the possibility of a new paradigm for the prevention and management of MSP and associated sickness absence approach at the workplace.