Background: Cardiomyocyte-specific knockout of pro-survival integrin β1 subunit and its downstream components have been demonstrated to aggravate remodeling after myocardial infarction (MI). However, as a component of integrin pathway, it is unclear whether knockdown of pro-survival C3G (rap guanine nucleotide exchange factor 1) in cardiac myocytes and fibroblasts could have effect on myocardial remodeling. Methods and results: A rat model of MI was established by ligation of left anterior descending coronary artery. Infarcted myocardium and its border zones in Sprague-Dawley rats were transiently infected with C3G knockout lentivirus via local injection to knockdown C3G in the myocardium. Twelve weeks after injection with the lentiviruses, cardiomyocytic apoptosis and collagen in surviving myocardium, and left ventricle (LV) end-diastolic diameter were decreased, whereas LV weight / body weight ratio and LV ejection fraction were increased in MI group via down-regulation of pro-survival C3G, phosphorylated (p) ERK1/2 (phosphorylated extracellular regulated kinase 1/2) and Bcl-2 (B-cell lymphoma-2), and up-regulation of pro-apoptotic Bax in the surviving myocardium. On the other hand, treatment with the lentiviruses was found to delete C3G and diminish cell proliferation in vitro cardiac myocytic and fibroblastic cell lines respectively via down-regulation of p-ERK1/2 and Bcl-2, and up-regulation of Bax. Conclusions: Knockdown of pro-survival C3G in myocardium may mitigate surviving myocardial remodeling after MI, possibly through regulation of p-ERK1/2, Bcl-2 and Bax in vivo cardiac myocytes and fibroblasts.