The malignant potential of oral lichen planus (OLP) has been a matter of serious controversy. We aimed to detect chromosomal numerical aberrations in cells of brush samples collected from affected mucosa. The samples were simultaneously analyzed for morphology and fluorescent in situ hybridization (FISH) with chromosomes 2 and 8 centromeric probes. We analyzed 57 persons with OLP and 33 control individuals. A cut-off value of aneuploid cells was determined as 1.1%. Aneuploid cells were found in 16 persons with OLP (28.1%); in 10 individuals (17.5%), over 5% of the cells were aneuploid. Aneuploid cells were also detected in normal-looking mucosa of seven persons with OLP. One person with OLP developed squamous cell carcinoma; 10% of the cells examined were aneuploid. OLP carries an increased risk for chromosomal instability. Identifying aneuploid cells in a brush sample and the combined morphological and FISH analysis can increase the specificity in predicting the malignant potential of OLP.