Acute myocardial infarction (MI) is associated with an adverse and sustained increase in cardiac sympathetic nerve activity (SNA), triggering potentially fatal ventricular arrhythmias. While myocardial reperfusion undoubtedly improves patient prognosis, it remains unknown whether reperfusion therapy also attenuates the dangerous increase in SNA. This study aimed to investigate the effect of time-dependent coronary reperfusion therapy on cardiac SNA following acute MI. Electrophysiological recordings of cardiac efferent SNA were performed in urethane-anaesthetized rats following ligation of the left anterior descending coronary artery (i.e., MI) for either 15 or 45 min, followed by ‘early’ or ‘delayed’ reperfusion, respectively. Another group of rats had permanent ischemia with no reperfusion. Forty-five minutes of ischemia induced a 55 % increase in efferent SNA. Subsequent ‘delayed’ reperfusion was ineffective at ameliorating further increases in SNA (maximal 153 % increase), so that MI-induced increases in SNA mirrored that observed in rats with permanent MI. Although SNA did not increase during 15 min of ischemia, it did significantly increase, albeit delayed, during the subsequent reperfusion period (max. 75 % increase). Importantly, however, this increase in SNA, which tended to be lower in the ‘early’-reperfusion group, was matched with a lower incidence of arrhythmias and mortality rate, compared to the ‘delayed’-reperfusion and permanent-MI groups. These results highlight that ‘prompt’ coronary reperfusion, before SNA becomes activated, may provide a crucial window of opportunity for improving outcome. Further research is essential to identify the mechanisms that underpin, not only sympathetic activation, but also importantly sympathetic deactivation as a potential therapeutic target for MI.