Background: Clostridium difficile infection is the leading cause of nosocomial diarrhea in the United States; however, few patients will develop fulminant C. difficile-associated disease (CDAD), necessitating an urgent operative intervention. Mortality for patients who require operative intervention is very high, up to 80% in some series. Since there is no consensus in the literature regarding the best operative treatment for this disease, we sought to answer the following:PICO [population, intervention, comparison, and outcome] Question 1: In adult patients with CDAD, does early surgery compared with late surgery, as defined by the need for vasopressors, decrease mortality?PICO Question 2: In adult patients with CDAD, does total abdominal colectomy (TAC) compared with other types of surgical intervention decrease mortality? Methods: A subcommittee of the Practice Management Guideline Committee of the Eastern Association for the Surgery of Trauma conducted a systematic review and meta-analysis for the selected questions. RevMan software was used to generate forest plots. Grading of Recommendations, Assessment, Development and Evaluations methodology was used to rate the quality of the evidence, using GRADEpro software to create evidence tables. Results: Reduction in mortality was significantly associated with early surgery, with a risk ratio (RR) of 0.5 (95% confidence interval [CI], 0.35-0.72). The quality of evidence was rated "moderate." Considering only the first procedure performed, mortality seemed to trend higher for TAC, with an RR of 1.11 (95% CI, 0.69-1.80). Considering only the actual procedure performed, the point estimate switched sides, showing a trend toward decreased mortality with TAC (RR, 0.86; 95% CI, 0.56-1.31). The quality of evidence was rated "very low." Conclusion: We strongly recommend that adult patients with CDAD undergo early surgery, before the development of shock and need for vasopressors. We conditionally recommend total or subtotal colectomy (vs. partial colectomy or other surgery) when the diagnosis of The Centers for Disease Control and Prevention is known. © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.