We conducted a prospective, randomized study to compare the efficacy of oral fusidic acid, oral metronidazole, oral vancomycin, and oral teicoplanin for the treatment of Clostridium difficile-associated diarrhea. Treatment resulted in clinical cure for 94% of the patients who were treated with vancomycin, 96% of those treated with teicoplanin, 93% of those treated with fusidic acid, and 94% of those treated with metronidazole. Clinical symptoms recurred in 16% of patients treated with vancomycin, 7% of those treated with teicoplanin, 28% of those treated with fusidic acid, and 16% of those treated with metronidazole. There was asymptomatic carriage of C. difficile toxin in 13% of patients treated with vancomycin, 4% of those treated with teicoplanin, 24% of those treated with fusidic acid, and 16% of those treated with metronidazole. No adverse effects related to therapy with vancomycin or teicoplanin were observed. Considering the costs of treatment, our findings suggest that metronidazole is the drug of choice for C. difficile-associated diarrhea and that glycopeptides should be reserved for patients who cannot tolerate metronidazole or who do not respond to treatment with this drug.