Vagal activity has protective effects in ischemic heart disease. We tested whether vagal stimulation (VS) could modulate the inflammatory reaction, a major determinant of cardiac injury after ischemia/reperfusion. Four groups of male rats underwent myocardial ischemia (30 minutes) and reperfusion (24 hours). One group underwent VS (40 minutes), 1 VS plus atrial pacing (VS + Pacing), and 1 VS plus nicotinic inhibition by mecamylamine (VS + MEC). After 24 hours, the area at risk, infarct size, inflammation parameters, and apoptosis were quantified. Infarct size was reduced in all VS-treated rats (controls, 53 ± 18%; VS, 6.5 ± 3%; VS + Pacing, 23 ± 6%; VS + MEC, 33 ± 9%; P < 0.005 vs. controls). The infarct size in the VS + MEC group was larger than that in VS-treated animals, despite similar heart rate, suggesting partial loss of protection. The number of macrophages, neutrophils, and apoptotic cells in the area at risk and the plasma cytokines levels were significantly reduced in all VS-treated animals. In conclusion, VS decreases infarct size and inflammatory markers during ischemia/reperfusion independent of the heart rate. The anti-inflammatory and antiapoptotic properties of the nicotinic pathway are the primary underlying mechanism. The vagally mediated modulation of inflammatory responses may prove valuable in the clinical management of acute coronary syndromes and of heart failure.