We aimed to assess the clinical efficacy of glucose-insulin-potassium (GIK) in acute myocardial infarction. Experimental data provided evidence of the beneficial effects of GIK on ischemic myocardium. The clinical trials, mostly uncontrolled and conducted mainly before the thrombolytic era, were inconclusive due to the small number of patients and discrepancies in protocols. In order to evaluate the efficacy of this intervention, we have performed a prospective multicenter randomized study. The study consisted of 954 patients with acute myocardial infarction (MI) randomized within 24 hours from the onset of symptoms to low-dose GIK (n = 494), which consisted of 1000 mL 10% dextrose, 32-20 U insulin, and 80 mEq K-, or to the control group (n = 460), which was given 1000 mL 0.89% sodium chloride, by intravenous 24-hour infusion at a rate of 42 mL/h. Cardiac mortality and the occurrence of cardiac events at 35 days did not differ between GIK and control-allocated patients (32 (6.5%) vs. 21 (4.6%), respectively; OR 1.45, 95% CI 0.79-2.68, P = 0.20; and 214 (43.3%) vs. 192 (41.7%), OR 1.07, 95% CI 0.82-1.38, P = 0.62). Total mortality at 35 days was significantly higher in the GIK than in the control group (44 (8.9%) vs. 22 (4.8%), respectively, OR 1.95, 95% CI 1.12-3.47, P = 0.01). The excess of non-cardiac deaths in the GIK group may have occurred by chance. Low-dose GIK treatment does not improve the survival and clinical course in acute MI.