Background: Clostridial myonecrosis is an uncommon, highly lethal necrotizing soft tissue infection. The source may be occult at the time of clinical presentation. In cases caused by Clostridium septicum, there is an association with colorectal malignant disease, suggesting that underlying colonic pathology frequently is the source of the infection. Methods: Case report and literature review. Case Report: A 37-year old man with acquired immunodeficiency syndrome, end-stage renal disease, and C. difficile colitis presented to the Emergency Department (ED) with a primary complaint of abdominal pain and incidental right forearm pain. While undergoing evaluation in the ED, he developed progressive erythema, edema, and emergence of bullae over his right forearm. After rapid imaging of his abdomen, he underwent guillotine amputation of his right upper extremity because of extensive myonecrosis and total abdominal colectomy secondary to right colonic necrosis and C. difficile colitis. Blood cultures were positive for C. septicum. Microscopic examination of both the necrotic colon and the right forearm musculature demonstrated invasion of gram-positive bacilli throughout. Conclusions: Myonecrosis caused by C. septicum frequently occurs in the presence of colonic pathology, typically malignant disease. This case report illustrates the development of this pathological process in an immunosuppressed patient who did not have colon cancer, but rather colonic mucosal inflammation produced by C. difficile.