The effects of moderate hyperthyroidism on insulin action were studied in five growing sheep (42 kg live weight [LW]) by the euglycemic hyperinsulinemic clamp technique, with insulin infused at rates of 0.33, 1.00, and 6.00 mU/kg LW/min over successive 2-hour periods. Animals were injected with saline (control) or thyroxine (15 micrograms/kg LW/d) for 21 days and measurements performed during the final 7 days of each period. Thyroxine (T4) treatment elevated plasma T4 less than threefold and plasma triiodothyronine (T3) twofold. T4 treatment elevated basal plasma glucose concentration (P less than .01) and insulin metabolic clearance rate at the highest rate of insulin infusion (P less than .05). The maximal insulin-induced increase in glucose metabolic clearance rate (responsiveness) was unaffected by T4 treatment, but the insulin concentration for a half-maximal response (sensitivity) was lowered during T4 treatment (122 v 58 microU/mL, P less than .05). Insulin infusion failed to completely suppress endogenous glucose output; T4 treatment had no effect. Insulin caused dose-dependent reductions in circulating concentrations of alpha-amino N, alanine, D-3-hydroxybutyrate, and glycerol, but not nonesterified fatty acids (NEFA). T4 treatment increased the sensitivity and responsiveness of alpha-amino N and alanine concentrations to insulin, the sensitivity of D-3-hydroxybutyrate (all P less than .05), and the responsiveness of glycerol to insulin (P less than .01). Thus moderate hyperthyroidism in growing sheep modifies the ability of insulin to regulate metabolism.