Cytoprotection or metabolic modulation is a new principle in the treatment of angina pectoris. The effect of ranolazine (a cytoprotective drug) on ischemic threshold, coronary sinus blood flow, and myocardial metabolism was evaluated by means of two pacing sequences in nine male patients with coronary artery disease (CAD) and in eight male controls. Ranolazine was given as an intravenous bolus followed by continuous infusion; the mean total dose was 32.7 mg and 31.7 mg in patients and controls, respectively. Angina pectoris was relieved in two patients after ranolazine but pacing time to pain was unchanged in the remaining patients. Maximal ST depression was lower (p = 0.02), but pacing time to maximal and to 1-mm ST depression remained unchanged after the drug. Ranolazine had no overall influence on coronary sinus blood flow, cardiac oxygen consumption, blood pressure, and heart rate. Cardiac uptake of free fatty acids (FFA) was reduced (p = 0.01), and net uptakes of glucose (p = 0.07) and lactate (p = 0.06) tended to be lower after ranolazine in CAD patients and controls. Ranolazine had no direct influence on cardiac exchange of glutamate, alanine, and citrate or on the arterial concentration of any metabolite. In the present study ranolazine had minimal clinical effects. A decrease in myocardial FFA utilization, however, allows greater myocardial glucose oxidation, which may increase the energy production in relation to oxygen availability.