The pharmacokinetics and pharmacodynamics of warfarin remained unaffected by tolvaptan during clinical trials. However, tolvaptan prolonged the prothrombin time–international normalized ratio (PT–INR) level of patients with cardiovascular disease taking warfarin. Tolvaptan was prescribed to 576 patients from December 2010 to December 2015. Of these patients, 37 underwent anticoagulant therapy. We investigated PT–INR fluctuation immediately before tolvaptan therapy was initiated. PT–INR remained unchanged in the control group and in groups administered with less than 7.5 mg/d tolvaptan, whereas it was significantly increased (p=0.03) in the group administered with more than 7.5 mg/d tolvaptan. This result indicates the possibility that tolvaptan affects the pharmacodynamics of warfarin in vivo. However, further research is necessary to clarify the mechanism of this phenomenon.