A 46-year-old male sought periodontal care for a swelling on his right mandibular gingiva. An excisional biopsy revealed a well-differentiated squamous cell carcinoma. Surgical treatment consisted of a right segmental mandibulectomy with ipsilateral right neck dissection and fibular free flap reconstruction. Two days after the surgical procedure, a weakened Doppler signal suggested vascular compromise of the graft. The patient was returned to the operating room where complete thrombosis of the internal jugular vein (recipient vessel) was observed. This event prompted a complete hematological evaluation that disclosed low serum levels of protein S. The patient was started on systemic heparin and local medicinal leeches. A week later, systemic warfarin sodium was added and successfully resolved the vascular compromise of the graft. Two years later, the patient is active and lives a full life with occasional adjustments of warfarin sodium. This case represents the first report on the treatment of gingival carcinoma that led to the serendipitous discovery of an unrelated and unusual systemic condition, protein S deficiency.