Introduction:Oral mucositis (OM) is a well-known complication of radiotherapy (RT) and chemotherapy (CT) in cancer patients. Although, 5-flourouracil (5-FU) is one of the standard cytotoxic therapies, it is one of the most common causes of OM, which results in delay, dose reduction or treatment discontinuation, thus this intensifies the need for an effective chemoprotective agent. We aimed to investigate the potential chemoprotective effect of growth hormone (GH) on 5-FU-induced OM in rats. Material & Methods:Rats were either exposed to a single 5-FU injection (160 mg/kg ip) and/or treated with GH (1 mg/kg s.c). Oxidative stress, inflammatory and apoptotic markers were assessed.Results: An array of mucosal damage was produced as a result of 5-FU injection, which was evident by histopathology. 5-FU induced a remarkable increase in lipid peroxidation accompanied with a significant depletion of glutathione level. Besides, inflammatory cascades, including NF-κB and IL-6, were elevated significantly. Furthermore, 5-FU stimulated cell death through the significant increase of caspase-3. Interestingly, Pre-treatment with GH markedly ameliorated the deleterious effects of 5-FU through counteracting the oxidative stress and inflammation-mediated apoptosis. In addition, GH rescued the oral mucosal histology following chemotherapy. Conclusions:Our study is the first to demonstrate evidences for the effective chemoprotection provided by GH against 5-FU induced OM along with the underlying mechanisms, which may offer a promising adjuvant therapy for cancer patients.