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Aim To analyse the cytomorphological features of keratinocytes in smears obtained from the oral mucosa of tobacco users and from oral squamous cell carcinoma lesions.Methodology Oral smears were obtained from clinically,normal appearing mucosa of oral squamous cell carcinoma patients (n=20) and from the mucosa of smokers (n=20),and apparently healthy individuals (n=20) were used as controls.The smears were histochemically stained and cytomorphological assessment of the keratinocytes was carried out.One-way ANOVA (Analysis of Variance) was used for comparing the parameters among multiple groups and Tukey-HSD test was used to compare the mean values between groups.Results The mean nuclear area of keratinocytes from the mucosa of tobacco users was 46±2.57 and that of the oral squamous cell carcinoma lesion was 81.54±4.31.While there was a significant (P=0.001) reduction in the cellular area of keratinocytes from oral squamous cell carcinoma lesion when compared with those from oral smears of tobacco users.Conclusion Cytomorphometric analysis of keratinocytes can serve as a useful adjunct in the early diagnosis of oral squamous cell carcinomas.