OBJECTIVE: Determine whether sleeping and resting energy expenditure and sleeping, resting, and 24-hour fuel use distinguish obesity-prone from obesity-resistant women and whether these metabolic factors explain long-term weight gain. RESEARCH METHODS AND PROCEDURES: Forty-nine previously overweight but currently normal-weight women were compared with 49 never-overweight controls. To date, 87% of the 98 women have been re-evaluated after 1 year of follow-up, without intervention, and 38% after 2 years. Subjects were studied at a General Clinical Research Center after 4 weeks of tightly controlled conditions of energy balance and macronutrient intake. Forty-nine obesity-prone weight-reduced women were group-matched with 49 never-overweight obesity-resistant controls. All were premenopausal, sedentary, and normoglycemic. Energy expenditure and fuel use were assessed using chamber calorimetry. Body composition was assessed using DXA. RESULTS: At baseline, percent body fat was not different between the obesity-prone and control women (33 +/- 4% vs. 32 +/- 5%, respectively; p = 0.22). Analysis of covariance results show that after adjusting for lean and fat mass, sleeping and resting energy expenditure of obesity-prone women was within 2% of controls. Neither sleeping nor resting energy expenditure nor sleeping, resting, or 24-hour fuel use was significantly different between the groups (p > 0.25). None of the metabolic variables contributed significantly to patterns of weight gain at 1 or 2 years of follow-up. DISCUSSION: The results suggest that when resting and sleeping energy expenditure and fuel use are assessed under tightly controlled conditions, these metabolic factors do not distinguish obesity-prone from obesity-resistant women or explain long-term weight changes.