Advances in microsurgery have resulted in high rates of free tissue transfer (FTT) success, with reports as high as 98% in highvolume centers. [1][2][3][4][5][6] Causes of flap failure include technical error, anastomotic thrombosis, vasospasm, hematoma, and unrecognized hypercoagulability. 1,[7][8][9][10][11][12][13][14][15] A hypercoagulable state is one of the most challenging preoperative conditions that reconstructive microsurgeons face.Background: Optimal perioperative thromboprophylaxis is crucial to avoid flap thrombosis and achieve high rates of microsurgical success. At the authors' institution, implementation of a risk-stratified anticoagulation (AC) protocol preliminarily showed a reduction in postoperative thrombotic events and flap loss. The authors present an updated analysis of surgical outcomes using riskstratified AC in thrombophilic patients who underwent free tissue transfer (FTT) reconstruction for nontraumatic lower extremity (LE) wounds. Methods: The authors retrospectively reviewed patients who underwent FTT to an LE from 2012 to 2021. Their risk-stratification AC protocol was implemented in July of 2015. Low-risk and moderate-risk patients received subcutaneous heparin. High-risk patients received heparin infusion titrated to a goal partial thromboplastin time of 50 to 70 seconds. Before July of 2015, nonstratified patients were treated with either subcutaneous heparin or low-dose heparin infusion (500 U/hour). Patients were divided into two cohorts (nonstratified and risk-stratified) based on date of FTT reconstruction. Primary outcomes included rates of postoperative complications, flap salvage, and flap success. Results: Two hundred nineteen hypercoagulable patients who underwent FTT to an LE were treated with nonstratified (n = 26) or risk-stratified (n = 193) thromboprophylaxis. The overall flap success rate was 96.8% (n = 212). Flap loss was lower among risk-stratified patients (1.6% versus 15.4%; P = 0.004), which paralleled a significant reduction in postoperative thrombotic events (2.6% versus 15.4%; P = 0.013). Flap salvage was accomplished more often in the risk-stratified cohort (80% versus 0%; P = 0.048). Intraoperative anastomotic revision (OR, 6.10; P = 0.035) and nonrisk stratification (OR, 9.50; P = 0.006) were independently associated with flap failure. Conclusions: Hypercoagulability can significantly affect microsurgical outcomes. Implementation of a risk-stratified AC protocol can significantly improve flap outcomes.