The effect of ingesting a meal containing 3,275 kJ (47.3% carbohydrate, two-thirds of which was in the form of simple sugars, 39.4% fat, and 13.2% protein) on the oxidation of carbohydrate fat and protein (or amino acids) was assessed by indirect calorimetry and measurement of the rate of excretion of nitrogenous end products in urine and changes in the plasma urea concentration. Simultaneously, an assessment was made of substrate metabolism in forearm muscle by measuring forearm blood flow and concentration of metabolites in arterialized and deep venous blood. The mean resting energy expenditure during the first four hours after food ingestion was 15% higher than in the preprandial period (P less than .01). The extra energy dissipated during this time is equivalent to 5.3% of the energy provided in the meal. Carbohydrate oxidation increased by 111% (P less than .01), protein oxidation increased by 40% (P less than .05), and fat oxidation decreased by 21% (P less than .05). The concentration of glucose and amino acids and their uptake by muscle increased after food ingestion, while the reverse occurred with nonesterified fatty acids (NEFA). In the early postprandial period there was a marked suppression in the uptake of NEFA by muscle and a tendency toward decreased rather than increased release of glycolytic products (lactate + pyruvate + alanine), despite an up to sevenfold increase in the uptake of glucose. Fructose, which accounted for about 30% of the carbohydrate in the diet, was not taken up by muscle to any significant extent. It is estimated that during the first four hours after the meal muscle accounted for the uptake of 20% to 25% of the carbohydrate provided in the meal. This was associated with a small and nonsignificant change in the oxygen uptake by muscle. The data suggest that: (1) the increased uptake of glucose by muscle in the postprandial period does not necessarily increase the release of glycolytic products or increase the activity of the glucose-alanine and Cori cycles between muscle and liver; (2) triglyceride may become a more important energy source for muscle than circulating NEFA, especially in the early postprandial period; (3) muscle is not a major site of dietary-induced thermogenesis (zero to four hours); and (4) it is likely that nonmuscular tissues took up more carbohydrate (including fructose) than skeletal muscle during the first four hours after ingestion of this meal (even if it is assumed that as little as 50% of the dietary carbohydrate had been absorbed by four hours).