Background: Cellular alteration is a unique feature during multi-step oral carcinogenesis. Non-keratinized normal oral squamous cells get keratinized in order to protect and preserve their normalcy in both structure and function. But, the pattern of keratinization seriously affects the nuclear-cytoplasmic ratio of the concerned cells. In the present study, the pattern of keratin expression and its impact on nuclear-cytoplasmic ratio in plump keratinized squamous cells during carcinogenesis was vividly analysed. Materials and Methods: Samples in the form of scraped and exfoliated cytosmear were collected from the affected sites of the clinically diagnosed 136 oral cancer patients and were immediately fixed in acetoalcohol (1:3). The wet fixed smears were stained by routine Papanicolaou’s staining protocol and Giemsa’s solution. Stained tissues were studied under the microscope. Results: Cytological pleomorphism is a unique feature observed during oral carcinogenesis and pattern of keratin expression in these pleomorphic cell reflect the cellular pathogenecity. Huge keratin expression in the cytoplasm of the plump keratinized squamous cells is presumed be to an important cause of alteration in the architectural regularity of the cell membrane which lead to cytological pleomorphism as well as a significantly (p<0.01) increase in nuclear- cytoplasmic (N/C) ratios from precancerous (1:27.9 in male and 1:28.9 in female) to cancerous (1:17.8 in male and 19.6 in female) cases during oral carcinogenesis. Conclusion: Pattern of keratin expression in well differentiated PKSCs is presumed to be a factor of cytological pleomorphism and increase in N/C ratio from precancerous to cancerous cases. Also, the appearance of PKSCs may be considered as a sign and index of cellular alteration in oral epithelia and a progenitor of cytological pleomorphism during oral carcinogenesis. And thus, the present finding has a practical utility in the field of diagnostic cytopathology in general and early detection of oral cancer during carcinogenesis in particular.