Background: To date, evidence for the efficacy of fecal microbiota transplantation (FMT) in recurrent Clostridium difficile infection (CDI) has been limited to case series and open-label clinical trials. Objective: To determine the efficacy and safety of FMT for treatment of recurrent CDI. Design: Randomized, controlled, double-blind clinical trial. (ClinicalTrials.gov: NCT01703494) Setting: Two academic medical centers. Patients: 46 patients who had 3 or more recurrences of CDI and received a full course of vancomycin for their most recent acute episode. Intervention: Fecal microbiota transplantation with donor stool (heterologous) or patient's own stool (autologous) administered by colonoscopy. Measurements: The primary end point was resolution of diarrhea without the need for further anti-CDI therapy during the 8-week follow-up. Safety data were compared between treatment groups via review of adverse events (AEs), serious AEs (SAEs), and new medical conditions for 6 months after FMT. Fecal microbiota analyses were performed on patients' stool before and after FMT and also on donors' stool. Results: In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]). All 9 patients who developed recurrent CDI after autologous FMT were free of further CDI after subsequent donor FMT. There were no SAEs related to FMT. Donor FMT restored gut bacterial community diversity and composition to resemble that of healthy donors. Limitation: The study included only patients who had 3 or more recurrences and excluded those who were immunocompromised and aged 75 years or older. Conclusion: Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.