Although persistent drainage and hematoma formation are recognized risk factors for the development of periprosthetic infection, it is not known if excess anticoagulation is a predisposing factor. We conducted a 2 to 1 case-control study with 78 cases who underwent revision for septic failure. The controls underwent the same index procedure but did not develop consequent infection. Patient comorbidities, medications, intraoperative, and postoperative factors were compared. Postoperative wound complications including development of hematoma and wound drainage were significant risk factors for periprosthetic infection. A mean international normalized ratio of greater than 1.5 was found to be more prevalent in patients who developed postoperative wound complications and subsequent periprosthetic infection. Cautious anticoagulation to prevent hematoma formation and/or wound drainage is critical to prevent periprosthetic infection and its undesirable consequences.