Levamisole is an increasingly common cocaine adulterant that can cause severe and rapid onset cutaneous vasculitis in humans. While most cases may be managed conservatively, we describe a series of patients in whom the extent of skin and soft tissue necrosis mandated surgical intervention. A retrospective review of all patients admitted to one of two regional burn centers between 2006 and 2016 for soft tissue necrosis after exposure to levamisole-adulterated cocaine was included in our study. Ten patients, majority female (9/10) with an average age of 43.4 years (range 31–57), were included. Cocaine usage before presentation averaged 6 days (range 1–14). Presenting complaints consisted of arthralgia (5/10), fever (7/10), and purpuric lesions (10/10). Average TBSA involvement was 23.5% (range 4–70). Immunological testing revealed perinuclear antineutrophil cytoplasmic antibody (pANCA+) in 8 of 10 and cytoplasmic antineutrophil cytoplasmic antibody (cANCA+) in 4 of 8 patients. Operative intervention occurred by postadmission day 11.6 (range 3–30). The mean number of operations required was 3 (range 2–6); length of stay averaged 46.8 days (range 14–120); and survival to discharge was 100% (10/10). To our knowledge, this is the largest case study detailing the surgical management of levamisole-associated skin necrosis. Additionally, we describe the most extensive case of this disease process at 70% TBSA involvement. Based on our experience, we recommend waiting for purpuric rash resolution and soft tissue necrosis to be fully demarcated before fascial debridement and then staged skin grafting with allograft followed by autograft.