To determine whether myocardial oxygen consumption (MVO2) might be reduced when myocardial substrate uptake is changed from predominantly lipid to predominantly carbohydrate, measurements of arterialcoronary sinus glucose, lactate, free fatty acids, oxygen, carbon dioxide and coronary sinus blood flow (by thermodilution) were obtained in 13 fasting patients. Measurements were initially made in a basal control state and then repeated at 10, 20 and 30 minutes during an infusion of glucose-insulin-potassium. After 30 minutes of infusion, there was a three-fold increase in myocardial glucose uptake (44 ± 10 to 145 ± 19 +μmoles/min [mean ± standard error of the mean], P < 0.01), a two-fold increase in myocardial lactate uptake (35 ± 4 to 77 ± 10 μmoles/min, P < 0.001) and a 75 percent decrease in myocardial free fatty acid uptake (34 ± 5 to 9 ± 3 μmoles/min, P < 0.01). Cardiac respiratory quotient rose from 0.70 ± 0.05 to 0.93 ± 0.08 (P < 0.001). Sum of oxygen extraction ratios for glucose and lactate rose from 51 ± 7 percent at control to 155 ± 22 percent at 30 minutes of infusion (P < 0.001) and suggested that much of the enhanced myocardial carbohydrate uptake met a nonoxidative fate, such as glycogen formation. During glucose-insulin-potassium infusion, arterial-coronary sinus oxygen decreased by 13 percent, coronary sinus blood flow increased by 12 percent and MVO2 was unchanged. The increase in coronary sinus blood flow was associated with a 13 percent decrease in coronary vascular resistance and a small, but significant, increase in serum osmolarity (289 ± 3 to 299 ± 3 mOsm/liter, P < 0.001). It is concluded that glucose-insulin-potassium infusion, while causing prompt alteration in myocardial substrate utilization from lipid to carbohydrate, produces no significant measurable change in myocardial oxygen consumption. However, such infusion is accompanied by a measurable increase in coronary sinus blood flow and a decrease in coronary vascular resistance. © 1977.