Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole-exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban-related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that inter-individual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.