Background:Autologous free tissue transfer is today an integral part of reconstructive plastic surgery, but still lacks generally accepted guidelines regarding antithrombotic agents. We hypothesized that the overuse of antithrombotic agents could be a risk factor for free flap complications and therefore studied a treatment protocol adjustment.Methods:Consecutive free flaps between 2005 and 2020 at a single center were analyzed for complications in relation to the use of pre- and intraoperative treatment with three different antithrombotic agents. The use of preoperative low molecular weight heparin (LMWH), intraoperative heparin, and dextran were analyzed in relation to outcome variables, thromboembolic events, or reexploration for hematoma.Results:Nine hundred thirty-one patients underwent 1000 microvascular free flaps for breast (n = 487), head and neck (n = 365), and extremity (n = 148) reconstruction. Within the first postoperative week, 44 cases had a thromboembolic event and 58 cases underwent hematoma-related reexploration. In the multivariate analysis, thromboembolic events were associated with extremity reconstruction (P= 0.02) and smoking (P= 0.02). Hematoma-related reexploration was more common with triple antithrombotic therapy compared with all other treatment regimes (P< 0.05). The number of antithrombotic agents used perioperatively was linearly decreased, from three to none, over the elapsed time period (P< 0.001).Conclusions:Hematoma was the most common reason for reexploration and was further associated with the use of multiple antithrombotic agents. Cessation of triple treatment was associated with less hematomas and further reduction of antithrombotic agents did not result in any increase of thromboembolic events. Evidence-based guidelines are warranted for antithrombotic regimes in standard free flap surgery.