Oral lichen planus (OLP) is a chronic muco-cutaneous inflammatory disease defined as a precancerous condition. We determined the expression patterns of proliferation markers topoisomerase IIalpha (topo IIalpha) and Ki-67 and an intermediated filament protein cytokeratin-19 (CK-19) in atrophic OLP. These markers were selected because our recent microarray analysis indicated they might aid in identification of potentially malignant lesions. The expression patterns were correlated with the DNA content of these lesions shown to be useful in detection lesions at risk for malignant transformation of OLP. A series of 81 formalin-fixed, paraffin-embedded biopsies from 70 patients suffering from atrophic OLP were immunostained with monoclonal antibodies against topo IIalpha, Ki-67 and CK-19 using standard methods. Of the 70 patients, there were eight patients who had dysplastic changes in OLP lesions. During the follow-up, altogether five patients got cancer in the OLP area even though no dysplastic changes were present in the preceding lesion. On light microscopy, 500 cells were examined in the basal and parabasal epithelial layers of biopsy samples at 400x magnification. All biopsy samples were topo IIalpha positive and approximately 70% of the counted cells were positive. Strong staining of topo IIalpha was significantly correlated with dysplasia (P = 0.019), basal cell hyperplasia (P = 0.005) and ulceration (P = 0.008) in the samples. Ki-67 was expressed in all samples but only 36% of the cells were positive. CK-19 positivity was found in 29% of the specimens. Histological parameters were not related to either Ki-67 or CK-19. The comparison of the staining patterns with the DNA content of lesions showed that strongly stained cells with topo IIalpha were significantly more frequent in the samples with 2.5cER higher than 15% than in those below 15% (P = 0.013; Mann-Whitney). The percentage of the measured cells is 2.5cER exceeding the 2.5c value on the DNA scale. We earlier showed that this cut-off value of 2.5cER discriminated DNA aneuploidy. To conclude, topo IIalpha is a proliferation and also an apoptotic marker in atrophic OLP lesions and it might have a predictive value in oral lichen planus lesions prone to develop malignancy.