Background: Both euthyroid sick syndrome and myocardial ischemia-reperfusion injury are common and have been significantly associated with morbidity and mortality after pediatric cardiac surgery with cardiopulmonary bypass. This single-center, prospective, double-blind, randomized placebo-controlled clinical pilot trial was designed to assess if preoperative oral thyroid hormone therapy could prevent the occurrence of euthyroid sick syndrome (ESS) and attenuate myocardial ischemia-reperfusion injury (IRI) after cardiac surgery with cardiopulmonary bypass (ORB) in children. Methods: Forty children aged 3 to 12 year, scheduled for elective congenital heart disease repair surgery with ORB, were randomized into 2 groups of equal size to receive the following treatments in a double-blind manner: placebo (control group) and thyroid tablet 0.4 mg/kg (trial group) taken orally once a day for 4 days before surgery. The perioperative serum thyroid hormone levels and hemodynamic variables were determined. The extubation time, duration of intensive care unit (ICU) stay, and use of inotropic drugs in the ICU were recorded. The myocardial expressions of heat shock protein 70 (HSP70), myosin heavy chain (MHO) mRNA, and thyroid hormone receptor (TR) mRNA were detected. The serum creatine kinase-MB (OK-MB) activity and troponin I (TnI) positive ratio at 24 hour after surgery were assessed. Results: There were no significant differences in hemodynamic variables at all observed points, extubation time, and duration of ICU stay between groups. As compared with baselines on administration, serum triiodothyronine (T-3) and free T-3 (FT3) levels on the first, second, and fourth postoperative day, and serum thyrotropic-stimulating hormone (TSH), tetraiodothyronine (T-4), and free T-4 (FT4) levels on the first postoperative day were significantly decreased in the 2 groups. Serum 13, FT3, and 14 levels on the first and second postoperative day, and serum FT4 level on the first postoperative day were significantly higher in the trial group than in control group. As compared with the control group, the number of patients requiring inotropic drugs in the ICU, serum OK-MB activity, serum positive TnI ratio, and myocardial expression of MHC beta mRNA were significantly decreased, and myocardial expressions of both HSP70 and MHC alpha mRNA were significantly increased in the trial group. Conclusions: In children undergoing cardiac surgery with ORB, preoperative oral small-dose thyroid hormone therapy reduces severity of postoperative ESS and provides a protection against myocardial IRI by increasing HSP70 and MHC alpha expression.