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Clostridium difficile colitis has increased in incidence and severity, and treatment failure with metronidazole therapy has increasingly been documented. It is uncertain whether treatment with vancomycin is more effective than treatment with metronidazole, but concern over the emergence of vancomycin resistance has motivated the search for alternative therapy. Nitazoxanide, a nitrothiazolide, blocks anaerobic metabolism of eukaryocyes and effectively treats intestinal infestation due to Cryptosporidium or Giardia species. At low concentrations, this compound inhibits C. difficile in vitro.We designed a prospective, randomized, double-blind study to compare nitazoxanide to metronidazole in treating hospitalized patients with C. difficile colitis.Thirty-four patients received metronidazole at a dosage of 250 mg 4 times per day for 10 days, 40 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 7 days, and 36 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 10 days. After 7 days of treatment, 28 (82.4%) of 34 patients had responded to metronidazole therapy, compared with 68 (89.5%) of 76 who had received nitazoxanide therapy (difference, 7.1%; 95% confidence interval, -7.1% to 25.5%). Thirty-one days after beginning treatment, sustained responses were observed in 19 (57.6%) of 33 patients who had received metronidazole therapy for 10 days, compared with 25 (65.8%) of 38 who had received nitazoxanide for 7 days and 26 (74.3%) of 35 who had received nitazoxanide for 10 days (P = .34).Nitazoxanide is at least as effective as metronidazole in treating C. difficile colitis.