Objectives:To study and compare the changes in nuclear and cellular size, shape and nuclear–cytoplasmic ratio of the cells in the basal layer of oral leukoplakia and well-differentiated oral squamous cell carcinoma (SCC) with normal buccal mucosa, using computer-aided image analysis in tissue sections.Study design:This was a retrospective study conducted on tissue sections on a total number of 70 cases to determine the various morphometric parameters. The data collected in this study were analyzed statistically by computing descriptive statistics, viz., percentage, mean, standard deviation, standard error of mean, 95% confidence interval for mean. The difference in the control and study groups for various diagnostic variables was compared by means of analysis of variance (ANOVA), Student’s t-test for independent samples, wherever applicable. Mann–Whitney U-test and Kruskal–Wallis test were used where the data were found to be asymmetrical and the standard deviations were also different. The results were considered statistically significant whenever P ≤ 0.05.Results:Our results were significant for the morphometric parameter, size. The values of nuclear perimeter and area, cellular perimeter and area increased gradually from the normal buccal mucosa to leukoplakia, reaching the highest value in SCC. There was statistically significant difference in the nuclear and cellular areas to differentiate between leukoplakia and squamous cell carcinoma. Two variables which were used to study the shape, “form perimeter (PE)” and “contour index (CI)”, showed significant difference between normal buccal mucosa and leukoplakia and between normal buccal mucosa and SCC. The morphometric parameter, nuclear–cytoplasmic ratio, in our results showed an increase in leukoplakia and SCC compared to normal buccal mucosa, but the difference was not significant between leukoplakia and SCC.Conclusion:The morphometric parameter, size, was useful to differentiate between normal, potentially malignant leukoplakia and SCC.