A large number of studies have reported that oxidative stress is important in the pathophysiology and development of HF via free radical production. Reactive oxygen species play a key role in the onset and progression of coronary heart disease, tissue necrosis, and contractile dysfunction. PRDX3 is a mitochondrial antioxidant protein that protects radical-sensitive enzymes against oxidative damage by a radical-generating system. Matsusshima et al. reported that PRDX3 overexpression protects the heart against post-myocardial infarct remodeling and failure in mice, reducing LV cavity dilation, dysfunction, fibrosis, and Semaxanib apoptosis. These results are consistent with our findings, since we found a significant increase in the protein levels of PRDX3 in the cardiac tissue of DCM patients probably due to its specific role in the attenuation mechanisms of these failing hearts. Although, we did not observe the same tendency between protein levels and gene expression, likely because of a different removal mechanism of this protein in failing hearts; however, the most remarkable finding was the good correlation between this protein level and LV function, indicating that an increased PRDX3 level is associated with impaired ventricular function. Thus, our findings demonstrated once again that mitochondrial oxidative stress is key player in the pathogenesis of cardiac failure and showed for the first time a direct relationship between the level of this antioxidant and LV dysfunction in human cardiac tissue, suggesting that it could be a primary line of defense against this disease process. With the objective to evaluate the causality of this significant relationship, further studies need to be done. It is noteworthy that our results are consistent and have been validated by different established techniques and by novel and precise SRM analysis and RNAseq approach. Despite these significant data, more work is needed to fully understand the causal role and which of the alterations observed are adaptive or maladaptive. A promising way to obtain leading to energetic derangement and, moreover, to restore ventricular function in DCM patients. For example, silencing or inducing overexpression of PRDX3 through gene therapy with the creation of a murine DCM model would allow us to investigate whether LV is aggravated or improved and to develop etiology-specific therapies in HF. In this way, we suggest new molecular targets and all these experiments could be providing a new therapeutic approach. A common limitation of studies that use cardiac tissues from end-stage failing human hearts is the fact that there is high variability in disease etiology and treatment. To make our study population etiologically homogeneous, we chose DCM patients who did not report any family history of the disease. Moreover, our tissue samples were taken from the transmural left ventricle apex, so our findings could not be generalized to all layers and regions of the left ventricle. However, we want to emphasize the importance of having carried out this study in a significant number of samples from explanted human hearts from DCM patients undergoing cardiac transplantation.