Rivaroxaban is a safer and more effective alternative to warfarin. However, there are reports of some cases of major hemorrhagic complications associated with rivaroxaban that significantly impair the patients' quality of life and can lead to a fatality. Personalized therapy, including pharmacogenetic testing, may help prevent such adverse events. This study aimed to investigate how ABCB1 3435C>T (rs1045642) and CYP3A5 6986A>G (rs776746) gene polymorphisms, when carried by a patient taking rivaroxaban to prevent thrombosis after total hip or knee replacement surgery, affect prothrombin time (PT). Sixty-five patients participated in the study. Their genotypes were identified by PCR in real time. To learn PT peculiar to each patient, we collected venous blood on the 5th day of their anticoagulation therapy, 1 hour before they took rivaroxaban and 3 hours after. Having calculated %ΔPT, we divided the patients into 2 groups: 1) %ΔPT ≤ 0 (n = 7; 10.8%); 2) %ΔPT > 0 (n = 58; 89.2%). Regarding the distribution of rs1045642 polymorphism, we determined the difference between the groups to be statistically significant (χ2 = 6.64; p = 0.027). As for rs776746 polymorphism, the difference was insignificant (χ2 = 0.101; p = 1.0). We discovered that rs1045642 polymorphism has a significant effect on PT variance in patients taking rivaroxaban to prevent thrombosis after total hip or knee replacement surgery.