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OBJECTIVE The objective of this study was to assess inflammatory cytologic alterations in the oral epithelium of patients on human immunodeficiency virus pre-exposure prophylaxis (PrEP). MATERIAL AND METHODS Epithelial cells from the buccal mucosa of 30 patients were collected by exfoliative cytology and were evaluated according to inflammatory cellular alterations: karyomegaly, bi- or multinucleation, karyopyknosis, karyorrhexis, perinuclear halo formation, metachromasia, cytoplasmic vacuolization, indistinct cytoplasmic border, keratinization, and atrophy. Epithelial cells were collected initially before PrEP onset (T1) and then after 30 days of PrEP use (T2). Two experienced cytopathologists independently analyzed the slides. RESULTS The nonparametric Wilcoxon test showed that there was a statistically significant increase in the number of cells with karyomegaly at T2 compared to T1 (P = .033). The other cellular alterations did not present with statistically significant differences between the 2 moments of evaluation (P > .05). CONCLUSION The increased number of oral epithelial cells with karyomegaly after 30 days of using PrEP suggests the presence of inflammatory alterations at this site.