Background: The natural history of thyroid function in adults with Down syndrome is relatively unknown with limited long-term follow-up data. Method: This study investigated annual thyroid function tests in 200 adults with Down syndrome over a 15-year period. Results: For healthy adults with Down syndrome there is a gradual increase in thyroxine and possible gradual decline in thyroid-stimulating hormone with age. The 15-year incidence for definite hypothyroidism remains low and subclinical hypothyroidism is not a precursor for the onset of definite hypothyroidism. Conclusions: The incidence of thyroid dysfunction is markedly less than would be expected from prevalence studies. Subclinical hypothyroidism is not necessarily a precursor to definite hypothyroidism. Prevalence studies have overstated the association between thyroid dysfunction and Down syndrome. Routine screening for adults with Down syndrome who are euthyroid can be reduced to every 5 years rather than the 1-2 years, as is the present policy.