Recently, a close relationship between the cell cycle and apoptosis was confirmed in oral squamous cell carcinoma (SCC). To clarify the expression of cell cycle-related proteins and apoptosis in the oral premalignant state, we investigated the expression of p27, cyclin D1 and proliferating cell nuclear antigen (PCNA) using immunohistochemical staining, and apoptotic index (AI) using ApopTag in situ staining. The positive expression-score of p27 was 42.0% in leukoplakia (34.8% in hyperplasia, 55.4% in dysplasia) and 31.1% in SCC (43.3% in the early stage of SCC, 25.9% in the advanced stage of SCC). The level of p27 expression showed a peak in dysplasia and decreased in SCC. The expression of cyclin D1 was almost constant between hyperplasia and SCC. The expression of PCNA increased sequentially with disease progression. The apoptotic index (AI) in the p27-positive leukoplakia group was significantly higher than that in the p27-negative leukoplakia group (3.9 +/- 3.6 vs. 1.5 +/- 1.6, p = 0.026). From these results, we suggest that the abundance of p27 in oral leukoplakia may inhibit cell proliferation and lead premalignant tumor cells to apoptosis, and thus is concerned with prevention of tumor progression.