Background: Obese persons generally regain lost weight, suggesting that adaptive metabolic changes favor return to a preset weight. Objective: Our objective was to determine whether adaptive changes in resting metabolic rate (RMR) and thyroid hormones occur in weight-reduced persons, predisposing them to long-term weight gain. Design: Twenty-four overweight, postmenopausal women were studied at a clinical research center in four 10-d study phases: the overweight state (phase 1, energy balance; phase 2, 3350 kJ/d) and after reduction to a normal-weight state (phase 3, 3350 kJ/d; phase 4, energy balance). Weight-reduced women were matched with 24 never-overweight control subjects. After each study phase, assessments included RMR (by indirect calorimetry), body composition (by hydrostatic weighing), serum triiodothyronine (T3), and reverse T3 (rT3). Body weight was measured 4 y later, without intervention. Results: Body composition-adjusted RMR and T3:rT3 fell during acute (phase 2) and chronic (phase 3) energy restriction (P < 0.01), but returned to baseline in the normal-weight, energy-balanced state (phase 4; mean weight loss: 12.9 ± 2.0 kg). RMR among weight-reduced women (4771 ± 414 kJ/d) was not significantly different from that in control subjects (4955 ± 414 kJ/d; P = 0.14), and lower RMR did not predict greater 4-y weight regain (r = 0.27, NS). Conclusions: Energy restriction produces a transient hypothyroid-hypometabolic state that normalizes on return to energy-balanced conditions. Failure to establish energy balance after weight loss gives the misleading impression that weight-reduced persons are energy conservative and predisposed to weight regain. Our findings do not provide evidence in support of adaptive metabolic changes as an explanation for the tendency of weight-reduced persons to regain weight.