Background The prevalence of hyperthyroidism and hypothyroidism is 0.5-4% in iodine-replete communities, but it is 5-10 times higher in women than in men. Those conditions are associated with a broad range of metabolic disorders and cardiovascular diseases. Biological evidence of a role of thyroid hormones in carcinogenesis also exists. However, the association between thyroid dysfunction and cardiovascular disease or cancer mortality risk remains controversial. In a large cohort of women, the associations of hyperthyroidism and hypothyroidism with cause-specific mortality were evaluated after nearly 30 years of follow-up. Methods The prospective study included 75,076 women aged 20-89 years who were certified as radiologic technologists in the United States in 1926-1982, completed baseline questionnaires in 1983-1998 from which medical history was ascertained, and reported no malignant disease or benign thyroid disease except thyroid dysfunction. A passive follow-up of this cohort was performed through the Social Security Administration database and the National Death Index-Plus. Cause-specific mortality risks were compared according to self-reported thyroid status, with proportional hazards models adjusted for baseline year and age, race/ethnicity, body mass index, family history of breast cancer, and life-style and reproductive factors. Results During a median follow-up of 28 years, 2609 cancer, 1789 cardiovascular or cerebrovascular, and 2442 other non-cancer deaths were recorded. Women with hyperthyroidism had an elevated risk of breast cancer mortality after 60 years of age (hazard ratio [HR] = 2.04 [confidence interval (CI) 1.16-3.60], 13 cases in hyperthyroid women) compared to women without thyroid disease. Hypothyroid women had increased mortality risks for diabetes mellitus (HR = 1.58 [CI 1.03-2.41], 27 cases in hypothyroid women), cardiovascular disease (HR = 1.20 [CI 1.01-1.42], 179 cases), and cerebrovascular disease (HR = 1.45 [CI 1.01-2.08], 35 cases, when restricting the follow-up to ≥10 years after baseline). Other causes of death were not associated with hyperthyroidism or hypothyroidism, though there was a suggestion of an elevated risk of ovarian cancer mortality in hyperthyroid women based on very few cases. Conclusion The excess mortality risks observed in a large, prospective 30-year follow-up of patients with thyroid dysfunction require confirmation, and, if replicated, further investigation will be needed because of the clinical implications. © Copyright 2017, Mary Ann Liebert, Inc. 2017.