Background: The role of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) is not well-known. Purpose: To assess the efficacy, comparative effectiveness, and harms of FMT for CDI. Data Sources: MEDLINE (1980 to January 2015), Cochrane Library, and ClinicalTrials.gov, followed by hand-searching references from systematic reviews and identified studies. Study Selection: Any study of FMT to treat adult patients with CDI; case reports were only used to report harms. Data Extraction: Data were extracted by 1 author and verified by another; 2 authors independently assessed risk of bias and strength of evidence. Data Synthesis: Two randomized, controlled trials (RCTs); 28 case-series studies; and 5 case reports were included. Two RCTs and 21 case-series studies (516 patients receiving FMT) reported using FMT for patients with recurrent CDI. A high proportion of treated patients had symptom resolution; however, the role of previous antimicrobials is unclear. One RCT comparing FMT with 2 control groups (n = 43) reported resolution of symptoms in 81%, 31%, and 23% of the FMT, vancomycin, or vancomycinplus- bowel lavage groups, respectively (P<0.001 for both control groups vs. FMT). An RCT comparing FMT route (n = 20) reported no difference between groups (60% in the nasogastric tube group and 80% in the colonoscopy group; P = 0.63). Across all studies for recurrent CDI, symptom resolution was seen in 85% of cases. In 7 case-series studies of patients with refractory CDI, symptom resolution ranged from 0% to 100%. Among 7 patients treated with FMT for initial CDI, results were mixed. Limitation: Most studies were uncontrolled case-series studies; only 2 RCTs were available for analysis. Conclusion: Fecal microbiota transplantation may have a substantial effect with few short-term adverse events for recurrent CDI. Evidence is insufficient on FMT for refractory or initial CDI treatment and on whether effects vary by donor, preparation, or delivery method.