BACKGROUND: This study evaluated the potential effects of beta-adrenoceptor (beta-AR) and natriuretic peptide receptor (NPR) gene polymorphisms on the susceptibility to and the severity of idiopathic dilated cardiomyopathy (IDCM) in a Chinese cohort. METHODS AND RESULTS: Ten polymorphisms in the coding regions of beta1-AR, beta2-AR, beta3-AR, NPR1, and NPR2 were genotyped in 430 IDCM patients and 468 healthy subjects. Patients with IDCM were followed for 2 years. In multi-loci combined subtype analysis, the combined profile of beta-AR and NPR was significantly different between IDCM patients and controls (P < .0001), mainly influenced by 2 loci beta1-Ser49Gly and NPR2-C2077T, which were also associated with the severity of IDCM. In single-loci analysis, allele frequencies of beta1-Gly49, NPR1-Glu939, and NPR2-T2077 were higher in patients with IDCM than in controls. Genotypes carrying NPR2-T2077 allele showed 1.94-fold independent risk for IDCM phenotype than C2077 homozygote (P < .001). Carriers of the NPR2-T2077 or beta1-Gly49 variant had worse New York Heart Association functional class or echocardiographic results and elevated serum brain natriuretic peptide, experienced severe symptoms, and required intensive medications and frequent hospitalization for heart failure. Furthermore, synergistic interactions between NPR2-C2077T and beta1-Ser49Gly were detected by multifactor-dimensionality reduction method. CONCLUSIONS: This study suggests that NPR2-T2077 and beta1-Gly49 polymorphisms may be genetically synergistic adverse factors for the susceptibility to or the severity of IDCM.