Objective. —To determine the safety and efficacy of a new combination treatment for patients withClostridium difficile—associated disease (CDD). The treatment combines the yeastSaccharomyces boulardiiwith an antibiotic (vancomycin hydrochloride or metronidazole). Design. —A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics andS boulardiior placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. Setting. —National referral study of ambulatory or hospitalized patients from three main study coordinating centers. Patients. —A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. Intervention. —Treatment with oralS boulardii(1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. Main Outcome Measure. —Recurrence of active CDD. Results. —A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated withS boulardiiand standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy ofS boulardiiwas significant (recurrence rate 34.6%, compared with 64.7% on placebo;P=.04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo;P=.86). There were no serious adverse reactions associated withS boulardii. Conclusions. —The combination of standard antibiotics andS boulardiiwas shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit ofS boulardiiwas demonstrated for those with an initial episode of CDD. (JAMA. 1994;271:1913-1918)