Experiments on dogs have shown that the size of the meal has no effect on the early cephalic postprandial thermogenesis, and that four small meals are more thermogenic than a larger meal with the same total caloric content as the four meals. A study was repeated on human subjects who were fed during alternating weeks either one large meal (653 kcal (1 kcal = 4.1855 kJ)) or four small meals (163 kcal) at 40-min intervals. Oxygen consumption and respiratory exchange ratio determinations indicated (i) larger overall increase in postprandial thermogenesis with the four meals than with one meal and (ii) an enhancement of glucose utilization with the large meal compared with greater lipid utilization with the four meals. On the basis of indirect evidence from previous investigations it is suggested that the enhanced thermogenesis observed in the four-meal experiment is due to lipid mobilization caused by repeated stimulation of the sympathetic nervous system with palatable food. Blood analysis indicated a reduced elevation of plasma glucose in the four-meal experiment. The variations of insulin and C-peptide exactly paralleled those observed for glucose. It is concluded that the increased frequency of feeding significantly reduces insulin secretion in subjects fed a relatively high carbohydrate meal. In addition to this beneficial effect, increasing the number of meals increased thermogenesis and fat utilization.