Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. It is the third leading causes of heart failure and the most common cause of heart transplantation due to its ventricular dilatation and contractile dysfunction. Currently, four hypothesized pathogenic mechanisms have been proposed: genetic predisposition, persistent cardiotropic viral infection, autoimmunity, and cell apoptosis. Presenilin-1 gene has been previously found to be associated with cell apoptosis and cardiac development. To assess the role of presenilin-1 in DCM, we examined two single nucleotide polymorphisms (SNPs) in presenilin-1 gene, namely, rs1800844 and rs177415. A total of 282 DCM patients and 306 controls were included in the study, and all SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Compared with controls, the frequency of AA and AC genotypes and the A allele at SNP rs177415 were significantly increased in DCM patients. No difference of the SNP genotype and allele frequencies at SNP rs1800844 was detected between DCM and control groups. Unconditional logistic regression adjusting for type 2 diabetes, hyperlipidemia, cigarette smoking, and gender, confirmed the association between that SNP rs177415 of the presenilin-1 gene and the susceptibility of DCM (adjusted OR 1.300, 95% CI 1.013-1.669; P = 0.039). Our data indicate, for the first time, the association of the presenilin-1 gene SNPs with human DCM and the allele A at SNP rs177415 in presenilin-1 gene may increase the risk of DCM.