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Purpose: Subclinical-thrombophilia contributes to delayed thrombotic complications/non-salvageability after free tissue transfer (FTT). Nevertheless, there is no consensus regarding optimal perioperative anticoagulation in these patients. We present our experience with lower extremity FTT in thrombophilic patients and compare outcomes for subcutaneous versus systemic anticoagulation protocols. Methods: Between 2012 and 2015, 52 patients with subclinical-thrombophilia underwent FTT for non-traumatic, lower extremity reconstruction. Patients were stratified into 2 main cohorts based on whether subcutaneous or systemic heparin was administered. Beginning day 0, patients were given daily aspirin (325-mg) and either (1) subcutaneous heparin (5,000-units every 8-hours), (2a) fixed-rate sub-therapeutic heparin infusion (500-units/hr), or (2b) titrated therapeutic heparin infusion (PTT 50-60). In the absence of complications, patients were converted to subcutaneous heparin on day 5 and continued on this regimen for a period of 3 weeks. Demographic data, reconstructive outcomes, and complications were retrospectively compared. Results: Twenty-seven patients were treated with aspirin/subcutaneous heparin, whereas 25 patients received aspirin/systemic heparinization with either fixed-rate (n=10) or titrated (n=15) heparin infusion. Flap loss (20% vs. 4%, p=0.066) and rates of thrombosis (16% vs. 7%, p=0.41) were higher among patients who received systemic heparinization. On subgroup analysis, failure rates were higher (26% vs 4%, p=0.027) following titrated systemic heparinization when compared to subcutaneous administration. Bleeding complications were also more prevalent among these patients when compared to those in both fixed-rate (13% vs 0%) and subcutaneous (13% vs 11%) cohorts. (p=0.22, 0.045). Conclusions: Prophylactic anticoagulation with aspirin/subcutaneous heparin is both safe and effective in thrombophilic patients who undergo lower extremity FTT. The risks of bleeding complications and thrombosis associated with systemic heparin do not justify its routine use in this population.