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Oral mucositis is a serious and debilitating side effect of cancer treatment. Greater understanding of the pathobiology of mucositis has recently led to the advent of targeted treatments for specific patient populations; however the treatment for mucositis remains palliative for most patients. Nuclear factor-kappaB (NF-κB) and cyclooxygenase 2 (COX-2) are thought to play important roles in the development of mucositis. In this study, 20 patients undergoing cytotoxic chemotherapy had oral mucosal biopsies taken prior to and following administration of cytotoxic chemotherapy. The samples were stained for NF-κB and COX-2 using routine immunohistochemistry. The results from this preliminary study demonstrated statistically significant increased oral mucosal staining for NF-κB and COX-2 following cytotoxic chemotherapy and provide further support for the role of NF-κB and COX-2 in the pathogenesis of mucositis.