Current American Academy of Pediatrics (AAP) Guidelines recommend monitoring thyroid function in infants with Down syndrome (DS) at birth, 6 and 12months, and annually thereafter. This study aimed to determine whether these guidelines are optimal for early diagnosis and treatment of (subclinical) hypothyroidism. Enrolled infants with DS less than age 7months, born at ≥ 30weeks gestation to monitor thyroid function test (TFT). A filter paper (FP) blood sample was analyzed for TSH and total T4 at ages 2 and 4weeks and monthly thereafter until 12months. Subjects with abnormal FP sample and confirmatory serum TFT for hypothyroidism promptly started treatment. Subjects with thyroid dysfunction identified had thyroid antibodies measured at diagnosis and 12months. Descriptive statistics determined average time to diagnosis of abnormal TFT. Sixteen (30%) of 54 subjects were diagnosed with a thyroid disorder, the majority with subclinical hypothyroidism (SH) and 1 with hyperthyroidism. Diagnosis occurred in 6 (11%), 9 (17%), and 12 (22.2%) infants in the first 30, 60, and 90days of life (DOL), respectively. Eight infants had an abnormal NBS and half were diagnosed with a thyroid disorder by DOL 8 and the remainder prior to 4months. Among subjects with a normal NBS, four were diagnosed at a mean of 104days and three at a mean of 101days prior to the 6-month and 12-month routine screens, respectively. Conclusion: Based on current AAP guidelines, thyroid disorder diagnosis would have been delayed in nearly 20% of the subjects. An additional TFT screen at 1 and 3months can lead to earlier diagnosis and treatment. What is Known: • Current American Academy of Pediatrics (AAP) Guidelines recommend thyroid function tests (TFT) in infants with Down syndrome (DS) at birth and 6 and 12 months. • Peer- reviewed retrospective studies report an increased incidence of hypothyroidism in infants with DS undetected by the newborn screen (NBS) and prior to 6 months. What is New: • This prospective study monitored TFT in infants with DS at age 2 weeks and monthly throughout the first year of life. • The findings in this study support additional TFT screens at 1 and 3 months in infants with DS.