© 2016 Vendome Group, LLC All rights reserved.Oral mucositis manifests as erythematous and ulcerative lesions of the oral mucosa. Among its various causes, cancer treatment (e.g., chemotherapy with or without radiation therapy) is one of the more well known. It has been widely mentioned that oxidative stress parameters such as lipid peroxidation levels increase during the cancer process. Glutathione is one of the major intracellular enzymes used to detoxify oxidant molecules; it exists in both a reduced and oxidized state. Reduced glutathione is used as a substrate to synthesize glutathione peroxidase. We conducted a study to investigate and compare the effects of triamcinolone (a synthetic steroid) and chlorhexidine (a chemical antiseptic) on 5-fluorouracil (5-FU; a chemotherapeutic agent)-induced oral mucositis in the buccal mucosa of 36 rats. Oral mucositis was induced through a combination of 5-FU treatment and mild abrasion of the cheek pouch with a wire brush. The rats were treated with one of four regimens: saline placebo (group I), 5-FU only (group II), 5-FU plus triamcinolone (group III), and 5-FU plus chlorhexidine (group IV). Three rats in the triamcinolone group died of unknown causes on days 7 and 8, and 3 rats in the chlorhexidine group died on days 7 and 9. On day 9, the remaining 30 rats were sacrificed and examined. Buccal mucosa lipid peroxidation levels were significantly higher in the 5-FU-only group than in the control group and significantly higher in the control group than in the triamcinolone group (p < 0.05 for both). Levels of reduced glutathione were significantly lower in the 5-FU-only group than in both the triamcinolone group and the chlorhexidine group (p < 0.05). Glutathione peroxidase activity was significantly higher in the triamcinolone group than in the 5-FU-only group (p < 0.01). Histopathologic analysis revealed that treatment with triamcinolone significantly reduced 5-FU-induced inflammatory cell infiltration and ulceration (p < 0.001); no such reduction was seen with chlorhexidine. In conclusion, we observed that triamcinolone and chlorhexidine treatment modulated chemotherapy-induced oxidative injury in rat oral mucositis. However, only triamcinolone histopathologically ameliorated 5-FU-induced oral mucositis. These findings suggest that triamcinolone is a useful agent for the management of experimental oxidative injury and oral mucositis caused by 5-FU chemotherapy.