The development of sepsis associated with a GI fistula can be a catastrophic complication of any surgical procedure in the vicinity of the abdominal cavity. The predominant sites of infection directly associated with GI fistulas are in the surgical wound and within the abdominal cavity. Some patients present with florid signs of sepsis, whereas others may have minimal signs of infection. CT scanning is the main diagnostic method for intra-abdominal collections. Often, it also provides a means of treatment by percutaneous placement of catheters. Patients who develop extensive cellulitis or necrotizing fasciitis, intra-abdominal collections incompletely drained by percutaneously placed catheters, multiple intra-abdominal collections not amenable to percutaneous drainage, dissociation of the ends of an anastomosis with flow of enteric contents into the peritoneal cavity, large intra-abdominal hematoma, or a septic course without identifiable source should be taken to the operating room on an urgent basis. The operative approach varies with the particular situation and extends from incision and drainage of the wound, extraperitoneal drainage of an abscess, and formal exploratory laparotomies, to the placement of tube enterostomies for decompression and drainage. The overall mortality of fistulas has decreased owing to better fluid and electrolyte replacement and the proper use of parenteral nutrition. However, patients continue to die from fistulas, and the cause of death is nearly always infection. The burden is on the surgeon to expeditiously diagnose and treat sepsis associated with GI fistulas.