In a prospective randomized placebo-controlled study, we assessed potential physiologic effects of nonthyroidal illness syndrome (NTIS) in acute illness. Coronary artery bypass graft surgery (CABG) was employed as a prospective model of acute illness and NTIS. Triiodothyronine (T3) or placebo was infused for 24 hours after surgery with a T3 dose selected to maintain postoperative serum T3 concentrations at preoperative levels. Patients were evaluated before CABG and during the postoperative period. Cardiovascular (CV) function was monitored with Swan-Ganz catheter measurements and ECG. Protein metabolism was evaluated with urinary nitrogen (U_N) excretion and L-[l-¹³C]leucine flux. Effects on sex steroid, growth hormone (GH)/insulin-like growth hormone 1 (IGF-1), and iron responses to illness were assessed with serum measurements of relevant hormones, iron, and total iron binding capacity (TIBC). CV function was not affected by T3 infusion except for a transient higher value of cardiac index in the T3 group 6 hours after surgery (3.04±0.12 for T3 and 2.53±0.08 for placebo; P=0.0016). Protein metabolism was not affected; changes in (U_N) excretion and L-[l-¹³C]leucine flux were equivalent in the two groups (P=0.35 and P=0.95 respectively). No differences were observed in changes in testosterone (T), estrogens, GH, IGF-1, iron, or TIBC between T3 and placebo groups. We conclude that in the early stages of major illness, the decrease in circulating T3 concentrations that occurs in NTIS has only a minimal transient physiologic impact on cardiac function, and plays no significant role in protecting against protein catabolism or modulating other endocrine responses or iron responses to illness.