Recent studies have suggested that probiotics or short chain fatty acids (SCFAs) exert a therapeutic effect on inflammatory bowel disease (IBD) patients. In a previous study, we demonstrated that Clostridium butyricum produces high levels of SCFAs in culture. In addition, a yogurt-based additive effectively masked, completely eliminating the unpleasant odor derived from the SCFAs. We recently reported that the oral administration of both high and low dose diets (50% w/w for 17 days and 5% w/w for 16 months, respectively) of the Clostridium butyricum derivative did not cause pathological abnormalities in rats. In the present study, we evaluated the effects of this product against dextran sulfate sodium (DSS)-induced experimental colitis in rats. Five-week-old male Wistar Hannover GALAS rats were given a mixture of a standard diet containing 3% (w/w) of DSS for 8 days. In the derivative-fed group, Clostridium butyricum derivative (20% w/w) with 0.1% (w/w) additive was also added to their diet. The control-fed group was given tap water (20% w/w) with 0.1% (w/w) additive. After 8 days, a laparotomy was performed, and macroscopic and microscopic inflammation scoring was determined. The Clostridium butyricum derivative effectively prevented bloody diarrhea. In addition, mucosal damage to the derivative-fed group was significantly reduced macroscopically compared to that of the control-fed group. The potential clinical efficacy of the Clostridium butyricum derivative in IBD patients is also discussed.