Growth hormone (GH) promotes protein anabolism and lipolysis. Its effects on glucose metabolism include suppression of glucose oxidation and may be associated with insulin resistance. In addition, GH stimulates energy expenditure (EE) and peripheral thyroid hormone metabolism. GH secretion is reduced in obese patients, but whether this is of pathophysiological significance is incompletely understood. In a double-blind placebo-controlled crossover design, we studied the effects of GH administration (0.03 mg · kg ideal body weight [IBW]-1 · d-1) on fuel metabolism, EE, and thyroid function in 10 obese women (age, 30.4 ± 2.4 years; body mass index [BMI], 37.0 ± 2.8 kg/m2, mean ± SE) with a normal prestudy oral glucose tolerance test (OGTT). Each treatment period (GH or placebo) lasted 5 weeks, separated by a 5-week washout period. At the end of each treatment period, subjects were studied in the basal state (8:00 am) and during a euglycemic glucose clamp including indirect calorimetry and isotopic measurement of glucose turnover. Lean body mass (LBM) was assessed at the end of each period by dual-energy x-ray absorptiometry. In the basal state, GH induced a significant increase in circulating levels of free fatty acids (FFA), glucose, insulin, and C-peptide. This was associated with a significant increase in resting EE (kcal/24 h, 1,934 ± 92 placebo v 2,323 ± 134 GH, P < .001), a decrease in the respiratory exchange ratio (RER), and increased rates of lipid oxidation (mg · kg LBM-1 · min-1, 1.55 ± 0.09 placebo v 2.20 ± 0.13 GH, P < .01). GH increased the rate of total basal glucose turnover, whereas oxidative glucose disposal was significantly decreased. Protein EE per kilogram LBM tended to decrease during GH treatment (P = .07). Furthermore, GH treatment was associated with changes in circulating iodothyronines, strongly suggestive of enhanced peripheral thyroxine (T4) to triiodothyronine (T3) conversion. During the clamp, GH administration caused insulin resistance in terms of elevated hepatic glucose production and a decreased rate of exogenous glucose infusion (mg · kg LBM · min-1 · min-1, 4.91 ± 0.84 placebo v 2.03 ± 0.34 GH, P < .01). All patients responded normally to an OGTT 4 weeks after completion of the study. We conclude that obese patients are highly sensitive to the lipolytic and calorigenic actions of exogenous GH; however, administration of exogenous GH is associated with a distinct resistance to the actions of insulin on glucose metabolism.