AIM: Late oral mucosa changes after radiotherapy for head and neck cancer have been poorly studied. This study aimed to determine long-term effects of radiotherapy on oral mucosa using exfoliative oral cytology. PATIENTS AND METHODS: Fifty patients with cancer were enrolled, five of whom in order to validate microscopic analysis. Smears were collected at programmed visit; a score was used to rank possible cytological alterations. Presence of inflammation was also microscopically described and compared to blood count tests. RESULTS: Epithelial cells revealed a peculiar 'folding' phenotype, not related to chemotherapy, total dose, or to the effective dose delivered to mucosa. Inflammation described was related to the score for 'folding' cells; moreover, score decreased in the presence of a higher lymphocyte count, while it was not altered by neutrophil count. CONCLUSION: We suggest application of exfoliative cytology to study radiation injury and the variability of individual response of oral mucosa to radiation.