Objective: To estimate the cost-effectiveness of periodic screening for mild thyroid failure by measurement of serum thyroid stimulating hormone (TSH) concentration., Design: Cost-utility analysis using a state-transition computer decision model that accounted for case finding, medical consequences of mild thyroid failure, and costs of care during 40 years of simulated follow-up., Setting: Periodic health examinations in offices of primary care physicians., Patients: Hypothetical cohorts of women and men screened every 5 years during the recommended periodic examination, beginning at age 35 years., Interventions: Adding the serum TSH assay to total serum cholesterol screening was compared to cholesterol screening alone., Main Outcome Measures: Discounted quality-adjusted life years (QALYs) and direct medical costs from a societal perspective., Results: The cost-effectiveness of screening 35-year-old patients with a serum TSH assay every 5 years was $9223 per QALY for women and $22595 per QALY for men. The cost-effectiveness became more favorable when age at first screening was increased for both sexes and was always more favorable for women than men. Reduced progression to overt hypothyroidism and relief of symptoms increased QALYs, but did not substantially reduce direct medical costs. Finding hypercholesterolemia induced by mild thyroid failure reduced direct medical costs, but did not substantially increase QALYs. The cost of a TSH assay and the importance to patients of symptoms associated with thyroid failure were the most influential factors in sensitivity analyses., Conclusions: The cost-effectiveness of screening for mild thyroid failure compares favorably with other generally accepted preventive medical practices. Physicians should consider measuring serum TSH concentration in patients aged 35 years and older undergoing routine periodic health examinations. The cost-effectiveness of screening is most favorable in elderly women.