In July 2012, metronidazole was approved for the treatment of Clostridium difficile infection (CDI). To clarify the selection criteria for the drug in terms of CDI severity, we established a diagnostic and therapeutic algorithm with reference to the SHEA-IDSA Clinical Practice Guidelines. We compared patients whose treatments were guided by the algorithm (29 cases, October 2012-September 2013) with patients treated prior to the development of the algorithm (37 cases, October 2011-September 2012). All cases treated with reference to the algorithm were diagnosed using enzyme immunoassay of C. difficile toxins A and B and glutamate dehydrogenase;an appropriate drug was prescribed in 93.1% of the cases. We found no significant between-group differences in the cure, recurrence, or complication rates. However, drug costs in cases wherein treatments were guided by the algorithm were markedly reduced. We have, thus, shown that algorithm-guided treatment is efficacious and cost-effective.