Objective To investigate the correlation between CYP2C19 gene polymorphisms and the incidence and prognosis of heart failure. Methods 1 368 patients who underwent parallel genomic testing and visited the Department of Cardiology at the People’s Hospital of Xinjiang Uygur Autonomous Region between June 2021 and December 2022 were selected. After quality control of genotype data, the patients were divided into a heart failure group and a control group based on diagnostic criteria. Genotyping of 31 genes and 62 single nucleotide polymorphism (SNPs) was performed using TaqMan-SNP genotyping technology. Differences in allele distribution and clinical indicators between the two groups were compared, and the incidence of cardiovascular adverse events in the heart failure group was followed up and calculated. Results A total of 1 352 patients were included. Among them, there were 169 cases in the heart failure group and 1 183 cases in the control group. At the rs12769205 locus of the CYP2C19 gene, the risk of disease for patients carrying the G allele was lower than those carrying the A allele (odds ratio=0.733, P=0.023). In addition to age, coronary heart disease, BMI, and the type of allele was also an independent influencing factor for heart failure (P＜0.05). Moreover, the level of cardiac troponin T in carriers of two mutant alleles was significantly higher than in carriers of one mutant allele (P =0.044) and in carriers of the wild-type allele (P=0.028). During the follow-up period, no significant differences were observed in the cumulative incidence of major cardiovascular adverse events among the three genotypes at the rs12769205 locus. Conclusion The polymorphic locus rs12769205 of the CYP2C19 gene is associated with the occurrence of heart failure, which may provide a theoretical basis for the diagnosis and treatment of heart failure.