Subclinical hypothyroidism (SCH) is a common condition (8-18%) among European older men and women. Although by definition SCH comprises biochemically mild thyroid hormone deficiency without overt symptoms, it is a likely contributor to multiple problems in older age. Thyroid hormone has multiple pleiotropic effects on numerous physiological systems, including the vascular tree, heart, skeletal muscle and brain. Therefore, thyroxine substitution to overcome thyroid hormone deficiency has the potential to give multi-system benefits to older people with SCH. Small studies have reported reduced atherosclerosis and improved cardiac function with thyroxine replacement, but no large clinical trials have been performed. Therefore the available evidence is limited, leading to major variations in guidelines and clinical practice, with uncertainty regarding the indications for screening and treatment.We are conducting a multicentre randomised placebo-controlled trial to assess the impact of thyroxine replacement. We have recruited 738 older adults with persisting SCH (excluding those in whom it is a temporary phenomenon who are less likely to benefit). We have included older men and women with a wide age range and of varying health status. Outcomes include health-related quality of life, cardiovascular events, muscle strength and executive cognitive function over 3-years of follow-up. We have the support of patient advocacy groups and a consortium with the wide range of expertise and experience required to conduct large-scale multicentre clinical trials.The proposal fits with the call, exploring the multi-system and quality-of-life benefits to older people of a tailored approach to management of SCH. This clinical trial should definitively clarify whether thyroxine treatment for SCH provides benefits that are relevant for patients. This trial will provide strong evidence with the potential to improve clinical practice, reduce healthcare costs and promote healthy ageing of European older adults.