Cytokeratins (CK) are the epithelia specific intermediate filament proteins. We have shown consistent non-expression of CK-5 protein in human oral pre-cancer and cancer, in earlier studies. To investigate whether non-expression of CK-5 protein is the result of transcriptional or translational block and to evaluate the possibility if CK-5 non-expression can be used as a marker for early diagnosis of tobacco related oral cancer, RT-PCR using CK-5 specific primers was conducted. Out of 36 precancerous lesions and 29 squamous cell carcinomas (SCC) of buccal mucosa (BM) samples studied, 11 and 13 samples respectively of precancer and SCC did not show CK-5 product in RT-PCR. Down regulation of CK-5 mRNA expression was also observed in some samples. Thus, in conclusion, our results have shown that CK-5 non-expression is the result of transcriptional block. We proposed CK-5 non-expression as a potential marker for the early diagnosis of tobacco related oral cancer.