Background/Aims: To determine the incidence and clinical characteristics of tuberculosis (TB) medication-associated Clostridium difficile infection. Methods: This multicenter study included patients from eight tertiary hospitals enrolled from 2008 to 2013. A retrospective analysis was conducted to identify the clinical features of C. difficile infection in patients who received TB medication. Results: C. difficile infection developed in 54 of the 19,080 patients prescribed TB medication, representing a total incidence of infection of 2.83 cases per 1,000 adults. Fifty-one of the 54 patients (94.4%) were treated with rifampin. The patients were usually treated with oral metronidazole, which produced improvement in 47 of the 54 patients (87%). Twenty-three patients clinically improved with continuous rifampin therapy for C. difficile infection. There were no significant differences in improvement between patients treated continuously (n=21) and patients in whom treatment was discontinued (n=26). Conclusions: The incidence of C. difficile infection after TB medication was not low considering the relatively low TB medication dosage compared to other antibiotics. It may not be always necessary to discontinue TB medication. Instead, decisions concerning discontinuation of TB medication should be based on TB status. (Gut Liver 2016;10:250-254)