: Pericardial effusion may be the first sign of congenital or acquired hypothyroidism and will completely resolve after thyroxin therapy. Hypothyroidism is more common in Down syndrome population than normal population. In this report we present four infants with Down syndrome who have pericardial effusion due to congenital hypothyroidism. All of these children with Down syndrome were admitted to our clinic with pericardial effusion. Pericardial effusion was completely resolved with thyroxin therapy without pericardiosentesis. Any child with Down syndrome who present with dyspnea and cardiomegaly should be suspected of having pericardial effusion due to hypothyroidism and echocardiography examination should be performed immediately. Pericardial effusion due to hypothyroidism will completely resolve with L-thyroxin therapy without pericardiosentesis. In conclusion, since a delayed diagnosis of hypothyroidism is likely and may favor the development of massive pericardial effusion and because of the difficult diagnosis of the hypothyroidism in Down syndrome, periodic follow-up of thyroid function tests are important.