Telomerase is a ribonucleoprotein complex with core units of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT). Telomerase activity is found in stem cells, germ cells and tumour cells but not in the majority of somatic cells. Telomerase activity is associated with cellular immortalization and tumorigenesis and this is generally due to the expression of hTERT, the catalytic subunit of telomerase. Objectives: To detect hTERT expression and telomerase activity and to correlate these with the histological progression of oral carcinogenesis. Methods: Specimens clinically diagnosed as potentially malignant oral lesions (n=8) and oral squamous cell carcinoma (n=14) were included in the study. Normal oral mucosa samples (n=5) were obtained from archival specimen collection. Analysis of hTERT expression levels on paraffin-embedded sections were done by immunohistochemistry (IHC) whilst Telomeric Repeat Amplification Protocol (TRAP) assays were performed on cultured cells and fresh tissues (15/27) to detect telomerase activity. Results: Dysplastic and neoplastic oral epithelia showed increased percentage of hTERT positive cells (Grade 4: >50% positive staining nuclei) with intense staining in superficial layers of the epithelia unlike normal oral epithelia which showed positive staining mainly in the proliferative progenitor compartments. Telomerase activity correlated with hTERT protein expression in tumour tissues but not in normal, hyperplastic and dysplastic tissues where telomerase was not detected with TRAP assays. Conclusion: There seems to be an up-regulation of hTERT expression with the progression of oral cancer and therefore indicates the feasibility of IHC detection of hTERT protein as a potential prognostic marker in oral carcinogenesis. Expression of hTERT seems to be an early event in oral cancer although its expression alone may not imply functional telomerase activity. This study is funded by Vote F 0213/03, University of Malaya and IRPA RMK-8 Grant [06-02-03-0174 PR 0054/05-05], MOSTE, Malaysia.