Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant$Arg \rightarrow Cys$missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular$Ca^2+-adenosine$triphosphatase (SERCA2a) pump. Transgenic$PLN^{R9C}$mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN,$PLN^{R9C}$did not directly inhibit SERCA2a. Rather,$PLN^{R9C}$trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.