Histopathological and immunohistochemical studies were conducted to elucidate the organization and remodeling of the extracellular matrix (ECM) and important factors in the early stromal reaction of oral precursor lesions and oral squamous cell carcinoma (OSCC). Gingivae from 36 cases (5 normal, 7 hyperkeratosis, 7 mild dysplasia, 7 moderate dysplasia, 5 severe dysplasia, and 5 OSCC) were examined. Histopathologically, hyperkeratosis demonstrated more desmoplastic areas than normal gingivae. Edematous changes and inflammatory cell infiltration were increased in cases of hyperkeratosis as compared to moderate dysplasia. Histo-morphological analysis revealed that the ratio of mature collagen stained by picro-sirius red was the most predominant in hyperkeratosis, and it decreased with advanced dysplastic grading. The greatest microvessel count occurred in moderate dysplasia, and the greatest microvessel area occurred in OSCC. Severe dysplasia and OSCC exhibited vasodilatation rather than increased microvessel count. The immunohistochemical analysis of ECM revealed that anti-collagen I had the most intense staining in hyperkeratosis, and the intensity of staining decreased with advanced dysplastic grading. The appearance of tenascin-c (tenascin) under the basement membrane was gradually increased from mild dysplasia to OSCC, and tenascin appeared scattered in the subepithelial zone of moderate dysplasia, severe dysplasia and OSCC. The up-reregulation of lysyl oxidase (LOX) and heparan sulfate proteoglycan (perlecan) in the subepithelial zone gradually increased along with the increase in dysplastic grading from moderate dysplasia to severe dysplasia to OSCC. Thus, in the present study of oral precursor lesions, inflammation, neovascularization and up-regulation of ECM-related proteins have reinforced from moderate dysplasia. Based on these results, it appears that moderate dysplasia is the stage at which the switch to malignant transformation occurs.