BackgroundThis study was performed to determine whether sick horses have thyroid hormone (TH) alterations similar to those observed in nonthyroidal illness syndrome in other species.HypothesisHorses suffering from systemic diseases have decreased THs and inappropriately low thyroid‐stimulating hormone (TSH).AnimalsSeventy‐one clinically normal horses; 380 hospitalized horses.MethodsTotal thyroxine (TT4), free thyroxine by equilibrium dialysis (fT4D), total triiodothyronine (TT3), free triiodothyronine (fT3), and TSH were measured in normal and hospitalized horses. Disease severity was categorized as mild, moderate, or severe by both subjective and objective criteria.ResultsNegative correlations existed between all THs, except TSH, and objective illness severity scores. These scores also increased with each subjective disease severity category. TT3 and fT3 were decreased with mild disease. TT3 progressively decreased more with moderate and severe disease. TT4 and fT4D remained normal with mild disease, but decreased progressively with disease severity. TSH increased with mild disease, but remained normal with moderate or severe disease. Horses that died or were euthanized had lower concentrations of all THs, except TSH, when compared with those that lived. In horses that received >3 doses of NSAIDs, corticosteroids, or heparin compared to 0–3 doses, TT3 and TT4 were decreased, whereas fT4D and TSH remained normal. There were minimal TH changes in horses that were not eating.Conclusions and Clinical ImportanceThyroid hormones decrease in horses with systemic disease. TT3 decreases first, followed by TT4 and fT4D. TSH fails to increase proportionally to the changes in THs, indicating hypothalamic–pituitary axis dysregulation. NSAIDs, corticosteroids, heparin, and fasting have less effect on THs compared with disease severity.