BACKGROUND: Oxyntomodulin has recently been found to decrease body-weight in obese humans and may be a potential anti-obesity therapy. OBJECTIVE: To determine whether oxyntomodulin alters energy expenditure, in addition to reducing energy intake, in 'free-living' overweight and obese volunteers. DESIGN: Randomized double-blind controlled cross-over trial. SETTING: Community and hospital-based. PARTICIPANTS: Fifteen healthy overweight and obese men and women (age: 23-49 years, BMI: 25.1-39.0 kg/m(2)). All volunteers completed the study protocol. INTERVENTIONs: Four-day subcutaneous self-administration of pre-prandial oxyntomodulin, three times daily. Participants were advised to maintain their normal dietary and exercise regimen. MEASUREMENTS: (1) Energy expenditure, measured by indirect calorimetry and combined heart rate and movement monitoring; (2) energy intake, measured during a study meal. RESULTS: Oxyntomodulin administration reduced energy intake at the study meal by 128+/-29 kcal (P=0.0006) or 17.3+/-5.5% (P=0.0071), with no change in meal palatability. Oxyntomodulin did not alter resting energy expenditure; but increased activity-related energy expenditure by 143+/-109 kcal/day or 26.2+/-9.9% (P=0.0221); total energy expenditure by 9.4+/-4.8% (P=0.0454) and physical activity level by 9.5+/-4.6% (P=0.0495). A reduction in body weight of 0.5+/-0.2% was observed during the oxyntomodulin administration period (P=0.0232). CONCLUSIOn: Oxyntomodulin increases energy expenditure while reducing energy intake resulting in negative energy balance. This data supports the role of oxyntomodulin as a potential anti-obesity therapy.