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Background: Individuals with resistance to thyroid hormone owing to mutations in the thyroid hormone receptor β gene (RTHβ) exhibit impaired tissue sensitivity to thyroid hormones, but retain sensitivity in cardiac tissue. Long-term health and survival outcomes in this rare disorder have not been evaluated. We investigated all-cause mortality and cardiovascular event risk in a cohort of patients with RTHβ, followed-up in UK endocrine clinics., Methods: In a retrospective cohort design, we linked genetically confirmed patients with RTHβ and age-matched and sex-matched population controls to outcomes in datasets within the Welsh Secure Anonymised Information Linkage (SAIL) Databank. Kaplan-Meier and Cox regression models analysed associations of RTHβ with all-cause mortality and cardiovascular events., Findings: We identified 61 patients with a genetic diagnosis of RTHβ between Jan 1, 1997, and Dec 31, 2019, and matched them with 2750 controls. Compared with controls, patients exhibited increased risks for all-cause mortality (hazard ratio [HR] 2·84, 95% CI 1·59-5·08), atrial fibrillation (10·56, 4·72-23·63), heart failure (HR 6·35, 95% CI 2·26-17·86), and major adverse cardiovascular events (MACE), comprising cardiovascular death, acute myocardial infarction, heart failure, or strokes (HR 3·49, 95% CI 2·04-5·99). The median age of first occurrence of any adverse event was 11 years earlier in patients (56 years, 95% CI 44-65) compared with controls (67 years, 65-70). Cubic spline analyses showed positive associations between FT4 concentrations at diagnosis and mortality or MACE, with FT4 concentration of 30 pmol/L or greater conferring increased risk. Compared with no intervention, treatment with antithyroid drugs, surgery or radioiodine gland ablation, or thyroxine did not control thyroid hormone excess., Interpretation: We have documented reduced survival and increased cardiovascular morbidity in a cohort of patients with RTHβ for the first time. These outcomes might be driven by lifelong cardiac exposure to thyroid hormone excess; and effective therapies, targeting hormone resistant pathways, could potentially curtail this risk., Funding: Royal College of Physicians, Wellcome Trust Investigator Award, and NIHR Cambridge Biomedical Research Centre., Competing Interests: Declaration of interests CM is an independent contractor to Egetis therapeutics, providing clinical perspectives on MCT8 deficiency and other potential rare diseases. She has received speaking fees from Bahrain Diabetes & Endocrine Review Conference, 2022, Qatar Diabetes, Endocrinology and Metabolic conference, 2022, Indiana University, USA, 2022, Indonesian society of Endocrinology meeting, 2022, 1st Annual Arab Thyroid Association Congress, 2022, European College of Veterinary Internal Medicine Annual Congress, 2021, Thyroid Disease, MSc Clinical Chemistry program, Trinity College Dublin 2016 to present. She is Chair, Study Review Committee on TRIAC withdrawal study (ReTRIACt), an international trial assessing effect of TRIAC withdrawal in patients with MCT8 deficiency. She is an expert endocrine advisor, Health products regulatory authority (HPRA), Ireland. She serves as Society for Endocrinology Program Committee Member (2019–2023). She was Secretary and Assistant Secretary, British Thyroid Association (2017–2022). She is Lead, European Thyroid Association Taskforce on Guidelines for Interference in Immunoassays of Hormones used in Thyroid Function Tests (2023 to present). She is Member of Committee, European Thyroid Association Guideline on Diagnosis and Management of Syndromes of Resistance to Thyroid Hormone. She is a member, expert working group on rare thyroid disorders for the European Reference Networks (2018 to present). She was National convenor, Society for Endocrinology Thyroid Network (2015–2020). CMD has received travel and accommodation fees for speaking at the symposium of the European Thyroid Association (Sept 2022). PNT is a member of the Clinical committee of the Society for Endocrinology and committee member of the British Thyroid Association. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)