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Proliferative verrucous leukoplakia is a unique type of oral leukoplakia that has a high risk of malignant transformation. The aim of this study was to examine the expression of transforming growth factor-alpha in proliferative verrucous leukoplakia, oral squamous cell carcinoma, and normal mucosa. Transforming growth factor-alpha, a potent mitogen, is known to play an important role in various neoplasms including oral squamous cell carcinoma. Immunohistochemical localization of transforming growth factor-alpha in archival paraffin-embedded sections was performed with commercially available monoclonal antibodies. Ten cases each of normal mucosa, proliferative verrucous leukoplakia, and oral squamous cell carcinoma were stained. Quantification of the staining intensity, expressed as the cytoplasmic optical density, was done with the Roche Image Analysis System. The data were statistically analyzed with the one-way analysis of variance and Tukey tests. Notably, the mean cytoplasmic optical density of proliferative verrucous leukoplakia was significantly higher than the mean cytoplasmic optical density of normal mucosa (p < 0.01). The mean cytoplasmic optical density of proliferative verrucous leukoplakia was slightly higher than that of oral squamous cell carcinoma, however, this difference was not significant (p > 0.05). The mean cytoplasmic optical density values demonstrate that increased transforming growth factor-alpha immunoreactivity occurs in proliferative verrucous leukoplakia and oral squamous cell carcinoma relative to normal mucosa.