ROS can signal fibrosis, and chronic hypertrophy is a key cause for LV dysfunction. We, therefore, examined if control of PARP1-dependent mitochondrial impairment and oxidative stress arrested cardiac remodeling and LV dysfunction in Chagas disease. Echocardiography imaging showed the LV mass and inter-ventricular septum thickness (IVS) were increased by 29–58%, while LV posterior wall (LVPW) was thinned by 31–47% in chagasic (vs. control) WT mice (Fig 6A–6E, all, p<0.05, S2 Table). Histological evaluation of tissue sections by Masson's Trichrome staining showed the myocardial collagen content was significantly increased in chagasic myocardium (score: 4.0 ± 0.4 vs. 0.3 ± 0.04, WT.Tc vs. WT, Fig 6F–6H, p<0.001). An increase in cardiac fibrosis in WT.Tc (vs. control) mice was also evidenced by 6-fold, 8-fold, and 1.5-fold increase in mRNA levels for COL1A1, COL3A1, and COL5A2, respectively (Fig 6I–6K, all, p<0.05). The chronically infected PARP1+/- and PARP1-/- mice exhibited the ability to maintain IVS and LVPW thickness at normal levels, >50% decline in collagen deposition, and 50–90% decline in the mRNA levels of collagen isoforms when compared to that noted in WT.Tc mice (Fig 6A–6K, all, p<0.05).