AbstractIntroductionIndividual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF).Materials and MethodsFrom June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496).ResultsThe bleeding events within 12 months were significantly related to the peak anti‐FXa level (p= .027).SUSD3rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14,p= 6.43×10−5). Five SNPs includingNCMAPrs4553122 (p= 2.29×10−5),PRF1rs885821 (p= 7.02×10−5),PRKAG2rs12703159 (p= 7.97×10−5),PRKAG2rs13224758 (p= 8.70×10−5), andPOU2F3rs2298579 (p= 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes includingGOT2rs14221 andMMP13rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy.ConclusionsPeak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban.SUSD3rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAPrs4553122,PRF1rs885821,PRKAG2rs12703159, rs13224758 andPOU2F3rs2298579) were suggestively associated with peak anti‐FXa level.