Single-dose oral administration of 100 mg caffeine increased the resting metabolic rate of both lean and postobese human volunteers by 3-4% (p less than 0.02) over 150 min and improved the defective diet-induced thermogenesis observed in the postobese subjects. Measurements of energy expenditure (EE) in a room respirometer indicate that repeated caffeine administration (100 mg) at 2-h intervals over a 12-h day period increased the EE of both subject groups by 8-11% (p less than 0.01) during that period but had no influence on the subsequent 12-h night EE. The net effect was a significant increase (p less than 0.02) in daily EE of 150 kcal in the lean volunteers and 79 kcal in the postobese subjects. Caffeine at commonly consumed doses can have a significant influence on energy balance and may promote thermogenesis in the treatment of obesity.