Objective:  To study the expression and role in vigabatrin (VGB)‐induced gingival enlargement of Ki‐67 antigen and p27KIP1, p21WAF1, and p53, proteins that activate or inhibit cell‐cycle progression.Materials and methods:  Six patients treated with VGB for partial epileptic seizures refractory to classic anticonvulsant treatment were studied. Gingival biopsies were taken from four of these patients for immunohistochemical studies; 10 control biopsies from individuals with healthy gingiva and 10 from patients with periodontal disease were also evaluated.Results:  Four of the six patients presented some degree of gingival enlargement (mild or moderate). Nuclear expression of Ki‐67 was elevated (mean of 894 positive cells/mm2 in VGB‐induced gingival enlargement vs. 391 cells/mm2 in controls with healthy gingiva and 425 cells/mm2 in controls with periodontal disease) (p < 0.01, analysis of variance: anova), and nuclear expression of cyclin‐dependent kinase (cdk) inhibitors p27KIP1 and p21WAF1 was reduced. The patients with gingival enlargement presented inflammatory infiltrate in lamina propria, mainly composed of T lymphocytes (CD3+) and plasma cells (CD38+), which was even more intense than in the biopsies of patients with periodontal disease.Conclusion:  The overexpression of antigen Ki‐67 and slight underexpression of cdk‐inhibitors p27KIP1 and p21WAF1 suggest that VGB induced an increase in cell proliferation and contributed, together with concomitant periodontal disease, to the gingival enlargement.