Reduced expression of sarcoplasmic reticulum calcium ATPase (SERCA)2 and other genes in the adult cardiac gene program has raised consideration of an impaired responsiveness to thyroid hormone (T3) that develops in the advanced failing heart. Here, we show that human and murine cardiomyopathy hearts have increased expression of friend of GATA (FOG)-2, a cardiac nuclear hormone receptor corepressor protein. Cardiac-specific overexpression of FOG-2 in transgenic mice led to depressed cardiac function, activation of the fetal gene program, congestive heart failure, and early death. SERCA2 transcript and protein levels were reduced in FOG-2 transgenic hearts, and FOG-2 overexpression impaired T3-mediated SERCA2 expression in cultured cardiomyocytes. FOG-2 physically interacts with thyroid hormone receptor-α1 and abrogated even high levels of T3-mediated SERCA2 promoter activity. These results demonstrate that SERCA2 is an important target of FOG-2 and that increased FOG-2 expression may contribute to a decline in cardiac function in end-stage heart failure by impaired T3 signaling.