Free fatty acids (FFA), the predominant myocardial energy substrate, are present in increased quantities immediately following acute myocardial infarction (AMI) and may cause deleterious alterations in cardiac rhythm, oxygen consumption, and mechanical performance. In an attempt to suppress FFA and simultaneously increase the availability of carbohydrate as a myocardial substrate, 70 patients with unequivocal AMI were administered a right atrial infusion of glucose-insulin-potassium (GIK) (300 gm. of glucose, 50 U. of regular insulin, and 80 mEq. of KC1 per liter of H2O) at a constant rate of 0.5 to 2.0 ml. per kilogram per hour for 48 hours. A dramatic fall in FFA (944 +/- 57 to 289 +/- 16 muEq per liter, p less than 0.0005) occurred during GIK infusion, and FFA rebounded to 420 +/- 39 muEq per liter (p less than 0.005) when GIK was discontinued. The hospital mortality rate in the 70 GIK recipients was compared to that of 64 untreated patients (controls) from the same coronary-care unit during the previous year. GIK and control groups had similar severity of infarction as assessed by prognostic scales of Killip, Peel, and Norris, respectively. The hospital mortality rate was reduced in the GIK recipients compared to the control group (11/70 vs. 19/64, p less than 0.05). In patients without history of prior myocardial infarction, the mortality rate was reduced four-fold in GIK recipients compared to controls (6 vs. 24 per cent, p less than 0.05). Complications of GIK infusion were infrequent and included chiefly hyperglycemia and hyperkalemia, both of which dictated meticulous monitoring of serum chemistries. The data suggest that suppression of plasma FFA with GIK infusion may be associated with a significant reduction in the hospital mortality rate of acute myocardial infarction.