 Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD. In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 00 days and then added either S. boulardii (0 g/day for 00 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose vancomycin (0 g/day) and S. boulardii (00.0%), compared with those who received high-dose vancomycin and placebo (00%; P=.00). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose vancomycin when either is combined with S. boulardii. 