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 → Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca²⁺–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.