The effects on total body oxygen consumption of nicotine infused intravenously and of simulated cigarette smoking were studied in intact anesthetized dogs. Nicotine infusion and simulated cigarette smoking raised total body oxygen consumption by 9 plus or minus 2% (mean plus or minus S.E.M.; P smaller than 0.02) and 6 plus or minus 2% (P smaller than 0.05), respectively, and arterial concentration of free fatty acids (FFA) by 29 plus or minus 9% (P smaller than 0.05) and 12 plus or minus 3% (P smaller than 0.01). When nicotine infusion and simulated cigarette smoking were repeated during inhibition of lipolysis with beta-pyridylcarbinol, no rise in total body oxygen consumption occurred, although the mean aortic blood pressure and heart rate remained elevated to levels similar to those during intact lipolysis. It is concluded that the rise in total body oxygen consumption induced by intravenously infused nicotine or simulated cigarette smoking was probably mediated through increased mobilization and consumption of FFA.