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Abstract: Background: As a transcription factor mainly expressed in cardiovascular system, T-box 20 (Tbx20) plays an important role in embryonic cardiovascular system development and adult heart function. Here, we determined the mechanism by which Tbx20 regulates cardiomyocyte apoptosis and cardiomyopathies. Methods: We analyzed Tbx20 expression levels and apoptosis rates in normal and heart failure human autopsy heart samples. Female C57BL/6 mice were ovariectomized and treated with 17β-estradiol to determine Tbx20 expression levels. ROS production, TUNEL, DNA laddering, qRT-PCR, Western blot, immunohistochemistry and ChIP analyses were performed on male C57BL/6 transverse aortic constriction-induced heart failure samples and on neonatal rat ventricular myocytes that were treated with H2O2 to investigate the role of Tbx20 in estrogen-mediated heart protection. Results: Tbx20 expression was down regulated during heart failure, accompanied by elevated cardiomyocyte apoptotic levels in humans and mice. H2O2 led to a concurrent decrease in Tbx20 expression and increase in apoptosis in cultured neonatal rat cardiomyocytes. Tbx20 overexpression reduced H2O2-induced cardiomyocyte apoptosis and was associated with a profound inhibition of p38MAPK, Bax and caspase3 and the activation of Bcl-2. Estrogen was able to protect cardiomyocytes from H2O2-induced apoptosis by upregulating Tbx20 expression in a concentration-dependent manner. Tbx20 silencing increased oxidative stress-induced apoptosis in H9c2 cells. Moreover, Tbx20 directly regulated Esrra expression to enhance the heart-protective effect of estrogen. Conclusions: These results indicate that Tbx20 functions as an important regulator of estrogen-mediated cardiomyocyte protection during oxidative stress, suggesting that estorgen-Tbx20-ERR-α may represent a crucial regulatory cascade and a potential therapeutic target for heart failure. [Copyright &y& Elsevier]