Thyroid peroxidase (TPO) is a key enzyme in the formation of thyroid hormones and a major autoantigen in autoimmune thyroid diseases. Titers of TPO antibodies also correlate with the degree of lymphocytic infiltration in euthyroid subjects, and they are frequently present in euthyroid subjects (prevalence 12–26%). Even within the normal range for thyrotropin (TSH), TPO antibody titers correlate with TSH levels, suggesting that their presence heralds impending thyroid failure. Assays for serum TPO antibodies have become much more sensitive, and very low titers can be found in virtually all subjects. However, titers above an assay-dependent cut-off are a clear risk factor for hypothyroidism; in the Whickham survey the annual risk of developing hypothyroidism in TPO-positive women with normal thyrotropin levels was 2.1%. Measuring TPO antibodies in euthyroid subjects can be used to identify subjects with increased risk for hypothyroidism: e.g. as triage to measure thyrotropin. This could be done in women who wish to become pregnant and those with an increased risk per se who are pregnant (to predict first trimester hypothyroidism, and postpartum thyroid dysfunction), patients with other autoimmune diseases, subjects on amiodarone, lithium, or interferon-⍺, and in relatives of patients with autoimmune thyroid diseases.