Background: Oral squamous cell carcinoma (OSCC) is the most devastating neoplasm with dramatic increase in morbidity and mortality. The detection and prognostic evaluation of precancerous lesions could aid in early control of cancer. Heat shock protein (HSP) 27 has found to be a biomarker and therapeutic target in different types of cancer. Aim: This study aims to investigate the role of HSP 27 as prognostic molecular indicator of malignant transformation in oral epithelial dysplasias. Materials and Methods: Thirty samples of epithelial dysplasia (10 mild dysplasia, 10 moderate dysplasia, and 10 severe dysplasia/carcinoma in situ cases), 10 samples each of well-differentiated OSCC and normal oral mucosa were routinely processed, formalin-fixed, paraffin-embedded, and analyzed for HSP27 expression by immunohistochemistry. Statistical analysis was done by one way-ANOVA and Mann–Whitney test to assess the differences between two individual groups. Results: Normal mucosa showed intense, but nonuniform, expression of HSP27. An initial decline was noted in dysplasias. A significant correlation of HSP27 expression was observed with the severity of dysplasia and well-differentiated OSCC ( P < 0.05). Conclusion: Low HSP 27 expression can be considered as early molecular indicator of initial dysplastic change in normal mucosa. An overexpression of HSP 27 in clinically and histologically confirmed dysplasia could indicate likely transformation to well-differentiated OSCC and could be of prognostic value. However, further studies with a larger sample size are required to confirm the role of HSP 27 as predictive indicator.