Abstract Background Health care workers have high physical work demands, involving patient handling and manual work tasks. A strategy for prevention of work-related musculoskeletal disorders can enhance the physical capacity of the health care worker. The aim of this study is to evaluate the efficacy of 'Tailored Physical Activity’ for health care workers in the Sonderborg Municipality. Methods/Design This protocol describes the design of a randomised controlled trial to assess the efficacy of 'Tailored Physical Activity’ versus a reference group for health care workers in the Sonderborg Municipality. Inclusion criteria to be fulfilled: health care workers with daily work that includes manual work and with the experience of work-related musculoskeletal pain in the back or upper body. All participants will receive 'Health Guidance’, a (90-minute) individualised dialogue focusing on improving life style, based on assessments of risk behaviour, on motivation for change and on personal resources. In addition, the experimental groups will receive 'Tailored Physical Activity’ (three 50-minute sessions per week over 10 weeks). The reference group will receive only 'Health Guidance’. The primary outcome measure is the participants’ self-reported sickness absence during the last three months due to musculoskeletal troubles, measured 3 and 12 months after baseline. In addition, secondary outcomes include anthropometric measurements, functional capacity and self-reported number of sick days, musculoskeletal symptoms, self-reported health, work ability, work productivity, physical capacity, kinesiophobia and physical functional status. Discussion The results from this study will contribute to the knowledge about evidence-based interventions for prevention of sickness absence among health care workers. Trial registration ClinicalTrials.gov: NCT01543984 .