Clostridium difficile (C. difficile) is a pathogen of major public health importance and the most common cause of healthcare-associated diarrhea, with high rates of recurrent disease, especially in those re-exposed to antimicrobial therapy. Data from the Centers for Disease Control and Prevention estimate that in 2011 there were 453,000 incident episodes of C. difficile infections (CDI) resulting in 29,300 deaths. The annual cost from CDI in the US is estimated at 1.3 billion dollars. Unfortunately, nearly one third of patients who develop initial infection will develop recurrence, and risk of subsequent recurrence increases with each episode. Antibiotics given for other infectious conditions may trigger CDI recurrence after resolution of initial CDI episode. Preventing CDI recurrence is essential to reduce the myriad physical, social, and psychological consequences that accompany recurrent episodes. Prophylaxis with vancomycin may reduce risk of recurrence but has not been well studied. We propose a multicenter placebo- controlled double blind randomized controlled trial (RCT) in 150 subjects to evaluate the efficacy of prophylaxis with 125 mg daily oral vancomycin versus placebo for preventing recurrent CDI in patients who have experienced at least one CDI episode in the last 90 days and are receiving antibiotics for a non CDI condition. In addition, we will evaluate the impact of this treatment on the gut microbiota composition and function and gut colonization by vancomycin-resistant enterococcus (VRE). Subjects will be followed for 8 weeks after completing vancomycin or placebo treatment. The primary outcome will be recurrent CDI. Procedures will include collection of at least 3 stool samples, and completion of stool diaries throughout the study with 3 study visits (baseline, completion of oral vancomycin and at 8 weeks following the end of therapy). Study findings will not only determine the efficacy of oral vancomycin prophylaxis, but also provide insight into the effect of oral vancomycin on the fecal microbiota and VRE colonization. With the critical importance of antibiotic stewardship, it is important to examine the trade-off between a potential benefit and possible adverse effects such as gut dysbiosis. If oral vancomycin prophylaxis is found to be efficacious it will shift the current paradigm in the approach to prevention of recurrent CDI.