Factor V Leiden is the most common genetic thrombophilia in people of European descent, and is important to recognize as it can have significant implications in dermatology. We report a case of a 30-year-old man who presented for evaluation and treatment of a chronic ulceration on the site of his stump following a below the knee amputation which had been performed for non-healing ulcerations. Despite a variety of treatments, his ulcer persisted. He was referred to a dermatologist who performed a biopsy that was interpreted as non-specific, and treatment was started for pyoderma gangrenosum. Further investigation revealed a homozygous factor V Leiden mutation and cryofibrinogenemia. He was tapered off of the methylprednisolone and was improving on stanozolol. He healed well after surgery and no new ulcerations have developed. This case highlights the importance of considering this mutation in a non-healing leg ulcer.