• Thyroid function in subjects with Down syndrome was studied using the thyrotropin-releasing hormone test. Forty-seven infants and children with Down syndrome were investigated. Ages ranged from 1 month to 7 years; there were 26 boys and 21 girls. Fourteen of the subjects with Down syndrome who had an exaggerated thyroid-stimulating hormone response to thyrotropin-releasing hormone stimulation had two or more annual follow-up tests. The remaining 33 subjects who only underwent one thyrotropin-releasing hormone test were compared with 22 age-matched controls (11 boys and 11 girls). Mean basal thyroxine 4 and triiodothyronine 3 values were in the normal ranges. All thyroid antibody titers were negative. Mean basal thyroid-stimulating hormone levels of subjects with Down syndrome were significantly higher than those of controls for all ages, even though there was a decline in thyroid-stimulating hormone levels in both groups. Peak thyroid-stimulating hormone response levels were significantly greater in the subjects with Down syndrome than in the controls. Longitudinal study of the 14 children with Down syndrome with an exaggerated thyroid-stimulating hormone response showed that the response remained exaggerated until the third year of life, when it declined to normal levels. Thyroid dysfunction during the growth spurt of infancy or delayed maturation of the hypothalamic pituitary thyroid axis are proposed mechanisms.