Background Both cardiac resynchronization therapy utilizing left ventricular (LV) epicardial pacing (EpiP) and mesenchymal stem cell (MSC) transplantation are potentially promising therapeutic modalities for the management of the advanced ischemic heart failure. We explored the efficacy and safety of combined LV EpiP and human MSC (hMSC) transplantation in canine model of acute myocardial infarction (AMI). Methods and Results AMI was made by ligation of proximal left circumflex coronary artery in open chest canine model, and positioned EpiP electrode on the peri-infarct zone for electrical pacing (DDD mode, 3.5 V, minimal AV delay 150 ms). Implantable cardioverter defibrillator (ICD) was implanted endocardially to monitor and treat ventricular arrhythmia. hMSC (1x10⁷ in 1 mL; n=3) or autologous bone marrow (BM in 1 mL, n=1) were injected subepicardially 15 mm apart from pacing electrode. One hMSC transplanted dog, in which neither AMI was made, nor pacing was turned on, was used as sham (Sham hMSC, n=1). After 14 days, we harvested the heart and histologic evaluation for human nucleus specific antibody stained cells. Results: 1. All 3 hMSC transplanted dogs suddenly died of fast ventricular tachycardia and electrical storm identified by ICD analysis at 2.7짹3.7 days after surgery. However, BM transplanted dog and sham hMSC dog survived for longer than 14 days. 2. There was no evidence of immune rejection in hMSC xenografted tissues. Human antigen expressing hMSC were observed at the subepicardial peri-infarct zone and showed mesodermal differentiation. Conclusion Although hMSC xenograft to canine AMI and epicardial pacing model showed successful engraftment of hMSC without immune rejection, sudden cardiac death because of electrical storm was frequently accompanied. Further study is required to assess 1) whether hMSC transplantation with epicardial pacing has proarrhythmic effect and 2) what their electrophysiologic consequence is.