With the introduction of broad-spectrum antibiotics into clinical practice, Clostridium difficile infection has become the most common cause of infectious diarrhea in hospitalized patients. Although mild cases may resolve by discontinuing antibiotics, thus allowing re-establishment of colonic microflora, oral metronidazole or vancomycin is indicated if the process is more severe. Metronidazole may be given intravenously, with intracolonic therapeutic levels achieved by excretion of drug into bile and exudation across inflamed tissue. Vancomycin is preferred treatment of severe cases. Bacitracin given orally is a therapeutic alternative and cholestyramine is a useful adjunct. Most patients with diarrhea or colitis caused by C. difficile respond to initial therapy; however, up to 20% experience relapse when treatment is discontinued. Repeating initial therapy for 10 to 14 days is indicated for first relapse. Multiple relapses require prolonged treatment with vancomycin, which may be supplemented with cholestyramine. Saccharomyces boulardii alone or in combination with vancomycin has been reported to be an effective therapeutic alternative for recurrent infection. Intravenous immunoglobulin can be effective in patients with severe recurrent Clostridium difficile colitis and immune deficiency or low pretreatment levels of serum antitoxin. Surgery is indicated only if recurrent infections are severe and associated with serious complications.