Background: It has been shown that cigarette smoking as well as diabetes mellitus can produce cytomorphometric alterations in oral epithelial cells with the significant increase in the nuclear area (NA) and significant decrease in the cytoplasmic/nuclear ratio in comparison to healthy control. However, the synergistic effect of tobacco smoking and diabetes on the morphology of gingival epithelial cells is not been explored until date. Aim: This study was carried out to investigate the effects of diabetes and the synergistic effects of smoking and diabetes on the cytomorphometry of gingival epithelium. Materials and Methods: Gingival smears were collected from 30 male subjects diagnosed with type 2 diabetes with (n = 10) or without history of smoking habit (n = 10). Healthy subjects with no history of smoking or diabetes served as the control group (n = 10). The smears were stained using Papanicolaou procedure. The cellular (CA) and nuclear areas (NA) were measured using image analysis software. One-way ANOVA and Tukey-HSD procedure (at P = 0.05) were used to analyze all the parametric variables. Results: A statistically significant (P < 0.001) increase in NA and N:C ratio in smoker diabetic group was observed compared to the non-smoker diabetic group and the control group. The non-smoker diabetic group also showed significant increase (P < 0.001) in NA and N:C ratio when compared to the control group, whereas the comparison of the three groups for difference in CA was not statistically significant at P > 0.05. Conclusions: There were significant alterations in the cellular pattern of gingival mucosa cells in a non-smoker diabetic, but the alteration was to a greater extent in smoker diabetics demonstrating a synergistic effect of smoking and diabetes on gingival mucosa.