Management of Clostridium difficile infection (CDI) involves discontinuation of the offending antibiotic agent as soon as possible. However, the ongoing infection does not allow discontinuation of the offending antibiotic. We aimed to retrospectively investigate the predictors of treatment failure and impact of the concomitant use of systemic antibiotics in patients receiving metronidazole therapy. This study was conducted among patients hospitalised at a second care academic hospital from January 2013 to December 2014. Eligible patients were identified by reviewing stool toxin enzyme immunoassay results for C. difficile. Diarrhoea was defined as the passage of at least three loose or watery stools within 24 h. Among 314 patients with CDI receiving metronidazole therapy, 62 (19.7%) showed treatment failure and 105 (33.4%) received concomitant antibiotics. Underlying dialysis, fever >38.3 °C, low median serum albumin levels and concomitant use of antibiotics were independent predictors of treatment failure in patients with CDI receiving metronidazole therapy. The concomitant use of antibiotics increased the rates of treatment failure and 30-day mortality in patients receiving metronidazole therapy. These results suggest that metronidazole should be used in mild cases of CDI only after discontinuation of the offending antibiotics.