to evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents.prospective multicenter study.101 DS patients with SH (TSH 5-10 mIU/L; FT4 12-22 pmol/L), aged 2-17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up.37/101 patients displayed autoantibodies positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, p=0.001; 32.4% vs 7.8%, p=0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, p=0.028). Gender, median BMI (SDS), height (SDS), FT4 and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (p=0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (p=0.02); 37.8% of group A vs 51.5% of group B still had SH condition (p=0.183). Logistic regression suggested autoimmunity (OR=3.2) and baseline TSH values (OR=1.13) as predictive factors of the evolution from SH to OH.In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.