Fidaxomicin causes less disruption of anaerobic microbiota during treatment of Clostridium difficile infection (CDI) than vancomycin and has activity against many vancomycin-resistant enterococci (VRE). In conjunction with a multicenter randomized trial of fidaxomicin versus vancomycin for CDI treatment, we tested the hypothesis that fidaxomicin promotes VRE and Candida species colonization less than vancomycin. Stool was cultured for VRE and Candida species before and after therapy. For patients with negative pretreatment cultures, the incidence of VRE and Candida species acquisition was compared. For those with preexisting VRE, the change in concentration during treatment was compared. The susceptibility of VRE isolates to fidaxomicin was assessed. Of 301 patients, 247 (82%) had negative VRE cultures and 252 (84%) had negative Candida species cultures before treatment. In comparison with vancomycin-treated patients, fidaxomicin-treated patients had reduced acquisition of VRE (7% vs 31%, respectively; P