Epidemiological evidence suggests that heavy consumption of betel quid and tobacco with areca nuts is the cause of high incidence of oral cancer in eastern part of Indian population, which is distinctly different from the etiology of oral squamous cell carcinomas (SCCs) in western countries. Here, expression of p53 and c-myc protein was studied in oral SCCs from this etiologically distinct population by immunohistochemistry. Out of 48 specimens of oral SCCs, 22 (45.8%) exhibited p53 positivity and 27 (56.3%) showed immunoreactivity with c-myc antibody. Considering the p53/c-myc expression pattern, either alone or in combination, the population was divided into four groups, i.e., both p53 and c-myc positive; p53 positive-c-myc negative; c-myc positive - p53 negative; and both p53 and c-myc negative. Tumours with both p53 and c-myc positivity were in advanced stages of the disease (poorly differentiated, tumour stage 3, nuclear grade III), whereas earliest stage of oral SCCs was detected in tumours with neither p53 nor c-myc immunoreactivity. Tumours of remaining two groups were generally restricted to early to moderate stages. These observations suggest that rapid progression of the betel- and tobacco-related oral SCCs may be associated with a simultaneous involvement of these two oncoproteins. The study also attempted to find out the relationship of p53/c-myc expression with spontaneous apoptosis. More apoptotic cells were found in c-myc positive but p53 negative tumours. This preliminary observation requires further molecular investigation of the role of p53 and c-myc genes for the progression of this epidemiologically distinct oral carcinogenesis.