Clostridium difficile colitis (CDC) remains a serious and common complication after liver transplantation (LT). Four hundred and sixty-seven consecutive LTs in 402 individuals were performed between 1998 and 2001 at our center. Standard immunosuppression consisted of tacrolimus, mycophenolate, and steroids. CD toxins A and B were detected by using a rapid immunoassay or enzyme immunoassay. CDC was diagnosed in 32 patients (5-1999 days post-LT), with 93.8% (30/32) of patients developing CDC during the first year post-LT; three individuals had CDC more than 3 years post-LT, one of which also had early CDC. All patients presented with abdominal pain and watery diarrhea. Patients who developed CDC within 1-year post-LT were significantly more likely to have a hemorrhagic, biliary, or infectious complication. Patients who developed CDC within 28 days post-LT had a significantly higher model end-stage liver disease score. Treatment consisted of fluid and electrolyte replacement and metronidazole and no patients developed toxic megacolon, required colonic resection, or died from CDC. CDC represents a potentially severe complication following LT. Most cases occur early post-LT. Development of a hemorrhagic, biliary, or infectious complication is associated with the development of CDC.