It was the objective of this study to quantify the effects of rivaroxaban administration on global coagulation parameters associated with routine clinical procedures, we collected plasma samples from patients undergoing major orthopaedic surgery receiving rivaroxaban at various time points after drug administration. Forty-seven patients received rivaroxaban (10 mg daily) for venous thromboembolism prophylaxis. Blood samples were collected at four different time points: A) before surgery; B) before drug administration at day 4-5 after surgery (steady state of rivaroxaban); C) 2 hours (h) after drug administration and D) 12 h after drug administration. The prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), antithrombin (AT) level, fibrinogen level by Clauss method (FibC), and derived fibrinogen (dFIB) level were assessed with various reagents. At 2 h after rivaroxaban administration, the PT and aPTT clotting times were significantly prolonged to different extents up to 1.4 fold, whereas 12 h after drug administration, no significant effect was observed. Rivaroxaban administration had no influence on the TT or the FibC concentration. The dFIB assay was differentially affected by rivaroxaban when different reagents were tested. The AT assay dependent on thrombin activity was not influenced by rivaroxaban, whereas the AT levels dependent on factor Xa activity were significantly increased by rivaroxaban. Clinicians should be aware of the time-dependent influence of rivaroxaban on factor Xa-dependent routine coagulation assays. Therefore, routine coagulation parameters should be assessed directly before drug administration to keep the interaction of rivaroxaban low.