Isolates of toxigenic Clostridium difficile, the most frequent cause of antibioticassociated pseudomembranous colitis, are almost always highly susceptible to rifampin. However, resistant isolates exist and have been associated with colitis in both hamsters and humans given rifampin. Rifampin is rarely implicated in the disease in humans; only six cases have been documented, all in elderly patients receiving treatment for tuberculosis. At least three of these patients had liver disease, and all six had also received one or more other antimicrobial agents. The only isolate of C. difficile from these patients that was studied was resistant to rifampin. The colitis was usually mild and responsive to discontinuation of treatment with rifampin or to oral treatment with vancomycin.