Energy expenditure was measured in a group of 7 subjects who received two isocaloric isonitrogenous diets for a period of 9-21 days with a 4-10-day break between diets. Diet 1 was a high-fat diet ( 83.5 +/- 3.6% of total energy). Diet 2 was a high carbohydrate diet ( 83.1 +/- 3.7% of total energy). Resting and postprandial resting metabolic rate were measured by open circuit indirect calorimetry 2-4 times during each metabolic period. Total energy expenditure (TEE) was measured by the doubly labeled water method over an 8-13-day period. The respiratory quotient was measured 2-4 hours after a meal during each metabolic period for the calculation of total energy expenditure by the doubly labeled water method. Levels of total T3 (TT3), T3 uptake, free thyroid index and T4 were measured at the end of each metabolic period. No significant changes in resting metabolic rate (RMR) were apparent on the two diets (1567 +/- 426 kcal/d high-fat diet and 1503 +/- 412 kcal/d high-carbohydrate diet n=7, p<0.15). Total energy expenditure measured in 5 subjects was significantly higher during the high-carbohydrate phase of the diet (2443 +/- 422 vs. 2078 +/- 482 kcal/d p<0.05). Activity estimated from TEE/RMR was greater on the high-carbohydrate diet but only approached statistical significance (p<0.06). Total T3 was significantly lower and free thyroid index and T3 uptake were significantly higher at the end of the high fat diet in comparison to the high-carbohydrate diet. These data suggest that individual tolerance to a high-fat diet varies considerably and may significantly lower TEE by changing levels of physical activity. The explanation for changes in thyroid hor. mone levels independent of changes in metabolic rate remains unclear.