Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Its effects are mediated by C difficile toxins A and B. Recent outbreaks of severe colitis have been associated with a new strain of the bacterium that produces large amounts of the toxins. Although oral metronidazole and oral vancomycin can be used to treat C difficile–associated disease, intraluminal vancomycin is preferable for more severe C difficile colitis. Early surgical intervention can improve outcomes with fulminant colitis, although overall mortality remains high.