Background and Objective: Oral submucous fibrosis is an inflammatory and a premalignant lesion as classified by "World Health Organization". Its pathogenesis is related to collagen metabolism. Bleomycin is an anti-carcinogenic drug, but it causes pulmonary fibrosis. This study was carried out to study the role of tumor necrosis factor alpha and keratin 17 in pathogenesis of oral submucous fibrosis.Study Design: Fifty pathologically-free female rats were divided into one control group and four test groups. They were injected by phosphate-buffered saline and Bleomycin into the buccal mucosae daily for 2, 4, 6 and 8 weeks, respectively. The histopathological changes was evaluated by studying the changes within epithelium tissue and lamina propria by (H&E) and the expression of both (tumor necrosis factor alpha and keratin 17) using immunohistochemistry and enzyme linked immunosorbent assay respectively. Results:The buccal mucosae of the test groups in comparison with control showed hyperplastic and hyperatrophic epithelial changes that gradually decreased with the severity of oral submucous fibrosis, with epithelial atrophy and focal dysplastic changes, which increase with severity of oral submucous fibrosis gradually. The lamina propria showed gradual increase in inflammatory cells, collagen formation and closure of the blood vessels. Regarding tumor necrosis factor alpha the area percent of immunoexpression, showed the lowest expression in the control and test groups showed gradually increase after 2, 4, 6,8 weeks within epithelium , on the other hand, the area percent of immunoexpression of tumor necrosis factor alpha within lamina propria showed gradually increase after 2, 4, 6 weeks, then decreased after 8 weeks. Regarding Keratin-17, the lowest value was recorded in control group while it increased gradually from the second week to the 8 th weeks. Conclusion:Both protein molecules tumor necrosis factor alpha and keratin 17 appear to be related in case of oral submucous fibrosis. As tumor necrosis factor alpha and keratin 17 are interdependent regulators, they could be used as diagnostic makers and a prognostic mirror of oral submucous fibrosis cases. Tumor necrosis factor alpha inhibitory drugs can be targeted in new therapeutic agents to improve the prognosis of oral submucous fibrosis.