Background: Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats. Methods and Results: At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325±6 vs. 355±10beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dt_max: +18%, P<0.01; left ventricular end-diastolic pressue: −26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73±0.04 vs. 3.06±0.08g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers. Conclusions: Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF.  (Circ J 2013; 77: 2519–2525)