Background: The safety of preoperative chemoprophylaxis for deep venous thrombosis (DVT) prevention in patients undergoing head and neck oncologic surgery with free tissue transfer (HNS-FTT) remains undetermined. Methods: Retrospective chart review of HNS-FTT patients receiving versus not receiving intraoperative subcutaneous enoxaparin (Px-LMWH) was performed. Outcomes included estimated blood loss (EBL), hematoma, flap compromise, DVT or pulmonary embolus (PE). Fisher’s exact test and Wilcoxon Rank Sum test were performed between groups (p-value < 0.05). Results: 44 of 134 patients (33%) received Px-LMWH. There was no significant difference in EBL, hematoma, or flap complications between groups. Patients without Px-LMWH had higher rates of DVT and PE (p = 0.999, 0.09, respectively). Conclusion: Px-LMWH can be used in major head and neck reconstructive surgery without increased intraoperative blood loss or postoperative complications. Larger studies will need to be done to determine the impact of Px-LMWH on DVT and PE in this patient population.