Thyrotropin (thyroid-stimulating hormone [TSH]) levels were elevated above 4.0 mU/L (μU/mL) in serum samples from 13.2% of 258 healthy elderly subjects. To investigate the natural history of progressive thyroid failure, serial thyroid functions were measured for four years in 26 of these subjects with elevated TSH levels. In one third of these subjects, biochemical thyroid failure developed (thyroxine level<58 nmol/L [4.5 μg/dL]) within the course of the study. All subjects with initial TSH levels above 20 mU/L (μU/mL), and 80% of those with high-titer thyroid antimicrosomal antibodies (regardless of initial TSH level), became overtly hypothyroid. Compared with subjects with high-titer antibody, those with antibody titer less than 1:1600 had lower TSH and higher thyroxine levels, and thyroid failure developed in none during the study. These results suggest that among older patients with isolated elevations of the TSH level, only those with markedly elevated TSH levels or high-titer antimicrosomal antibodies should be prophylactically treated with levothyroxine sodium replacement.