Abstract Background The activation of cardiac sympathetic nervous system is associated with poor prognosis in patients with acute myocardial infarction (AMI). However, it remains to be determined whether regional assessment of cardiac sympathetic nerve activity (CSNA) in the culprit and non-culprit lesion of the cardiac MIBG SPECT imaging could have prognostic value in patients with AMI. Purpose The purpose of this study is to investigate the prognostic impact of regional CSNA in patients with AMI. Methods We prospectively enrolled 122 patients with AMI who visited our emergency department and underwent primary percutaneous coronary intervention. The late heart-to-mediastinum ratio (HMR) and washout rate (WR) was calculated to assess CSNA in the whole heart from planar images of in the cardiac MIBG imaging. The MIBG SPECT image parameters were calculated for each coronary artery, and the average WR in the culprit and non-culprit lesion were evaluated to assess the regional status of CSNA in patients with AMI. Abnormal WR in planar image was defined as 34% or more, as previously reported. The cut-off value of late HMR in planar image, WR in the culprit and non-culprit lesions were determined by ROC analysis. The primary endpoint was major adverse cardiac event (MACE) including all cause death, myocardial infarction, hospitalization for heart failure and target lesion revascularization. Results During a mean follow-up period of 3.1±1.8 years, 25 of 122 patients underwent MACE. The late HMR (p=0.004), WR in planar image (p=0.002), WR in the culprit lesion (p=0.023), and WR in the non-culprit lesion (p<0.001) were significantly associated with MACE at univariate Cox proportional hazard analysis. The increased WR in the non-culprit lesion (defined as 28.3% or more: AUC 0.697 [0.576-0.817]) was significantly independently associated with MACE (hazard ratio: 4.36 [1.45-13.11], p=0.009) even adjusted by late HMR, WR in planar image or WR in the culprit lesion, while decreased HMR, abnormal WR in planar image and increased WR in the culprit lesion showed no significant association with MACE in the multivariate model with WR in the non-culprit lesion. Kaplan-Meier analysis revealed that patients with increased WR in the non-culprit lesion had significantly higher risk for MACE than those without increased WR (45% vs 11% p<0.001). Conclusion(s) The activation of cardiac sympathetic nervous system in the non-culprit lesion is particularly associated with poor prognosis in patients with acute myocardial infarction.MACE risk by WR in non-culprit lesion