Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes ( , , , , ) with the risk of bleeding from DOACs in non-valvular AF patients. A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus -values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all > 0.1). In exploratory analyses with other genetic models, the (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban HR: 1.391 (95%CI: 1.019-1.900); = 0.038 but not from apixaban ( = 0.487). Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.