The presence of high risk human papilloma virus (HPV) 16 and 18 was examined in 100 oral cancer patients of Indian descent, 80 patients with potentially malignant oral lesions and corresponding clinically normal mucosa from 48 of these patients. Additionally, presence of HPV-33, -6 and -11 was also studied in 86 oral cancers, 50 potentially malignant oral lesions and 30 corresponding normal oral mucosa. All the patients with oral cancer and oral lesions, were long term tobacco-chewers, and a majority of the patients were in Advanced Stages III and IV. The DNA samples were amplified by polymerase chain reaction (PCR) using HPV L1 consensus primers. Typing of HPV was performed by Southern hybridization analysis of the PCR products using HPV-16, -18, -33, -6 and -11 type specific oligonucleotide probes. HPV-16 was detected in 15 out of 100 (15%) oral tumours, 27 out of 80 (34%) potentially malignant lesions and 15 out of 48 (31%) of the corresponding normal mucosa in the patients with oral lesions. HPV-18 was not detected in any of the oral cancers, oral lesions and normal mucosa. HPV-33 and the low-risk HPV-6 and -11 were also not detected in the oral cancers, oral lesions and corresponding normal mucosa. A significantly higher prevalence of HPV-16 was observed in oral lesions (27 out of 80, 34%) as compared to oral cancers (15 out of 100, 15%). The observed difference of 19% (95% confidence interval [CI]: 6%, 31%), between these two proportions was statistically significant at the 5% level of significance. Our data indicates that HPV-16 may play a direct role in a certain proportion of oral cancers; whereas in a subpopulation of oral cancers HPV-16 infection may be vital in the early events associated with development of potentially malignant oral lesions, and the presence of the virus not essential in the progression of the oral lesion to frank malignancy.