Background: Oxidative stress and accumulation of reactive oxygen species may play a role in the pathogenesis of cancer. They were reported in precancerous and cancerous cells.   Methods: An animal model of carcinogenesis was used to detect the effect of oxidative stress on mitochondrial ultrastructure by transmission electron microscope and the levels of extracellular signal- regulated kinase-1(ERK-1) and hypoxia inducible factor-1 alpha (HIF-1α) by immunohistochemistry in mild and severe oral epithelial dysplasia (OED) induced in tongues of experimental mice.   Results: We identified degeneration and enlargement of mitochondria in association with up- regulation of both ERK-1 and HIF-1α from normal control to mild OED and reached their highest values in severe OED.   Conclusions: Degeneration and enlargement of mitochondria in association with up-regulation of both ERK-1 and HIF-1α can be indicative features of dysplastic changes and may act as early markers for malignancy.