As the European population is ageing rapidly, the growing number of seniors with age-related chronic diseases poses a challenge on European societies and health care systems. Therapeutic interventions that are effective, affordable and well-tolerated in the prevention of chronic disease are urgently needed and will have an outstanding impact on public health as a whole. Among the most promising interventions that meet these requirements are vitamin D, marine omega-3 fatty acids and physical exercise. However, their individual and combined effects have yet to be confirmed in a clinical trial. The DO-HEALTH will close this knowledge gap in a large 3-year multi-centre clinical trial that will establish long-term efficacy and safety data for the 3 interventions in the prevention of age-related diseases in seniors.The DO-HEALTH trial will enrol 2152 community-dwelling men and women aged 70 and older, when chronic diseases increase substantially. The randomized-controlled trial will test the individual and the combined benefit of 2000 IU vitamin D/day, 1 g of omega-3 fatty acids/day and a simple home exercise program in an efficient factorial trial design. DO-HEALTH will establish evidence in 5 primary endpoints: the risk of incident non-vertebral fractures; the risk of functional decline; the risk of blood pressure increase; the risk of cognitive decline; and the rate of any infection. Key secondary endpoints include risk of hip fracture, rate of falls, pain in symptomatic knee osteoarthritis, glucose tolerance, gastro-intestinal symptoms, mental and oral health, quality of life, and mortality. Follow-up will be in-person, in 3-monthly intervals (4 clinical visits and 9 phone calls). DO-HEALTH will further assess the comparative effectiveness of the interventions by evaluating reasons why or why not seniors adhere to them, and will assess their cost-benefit in a health economic model based on documented health care utilization and observed incidence of chronic disease.