Diagnosing and prognosis of oral cancer precursors is challenging. This study investigates the correlation quantitative and qualitative expression of p16 in HPV positive and HPV negative OSCC cases .Human Papillomavirus (HPV) is believed to promote the oncogenic process and the correlation between viral oncoproteins and dysfunction of p16 tumour suppressor protein in oral lesions has been established in many studies .Concerning involvement of risk factors ,clinical course of the disease ,and prognosis there are strong indications arguing that the HPV positive OSCC may represent a separate tumour entity. Looking for a surrogate marker ,which in further epidemiological studies could replace the laborious and expensive HPV detection methods this study was conducted which include 30 cases of HPV positive and 30 HPV negative OSCC and 10 controlled cases of HPV colon were taken and p16 was evaluated according to distribution extent and degree of intensity.Based on the staining intensity among the HPV negative cases the staining intensity score was 1 in 80 percent of the subjects whereas in the HPV positive cases 63.3% were having Score 3 and 26.7% were having Score 2. The difference between HPV+ and HPV- was statistically significant and was analyzed using chi square test.Based on the semi quantitative analysis among the HPV negative cases the staining was negative in 80 percent of the subjects whereas in the HPV+ 63.3% were having diffuse staining and 30.0% were having focal staining. The difference between HPV positive and HPV negative was statistically significant when analyzed using chi square test.These data indicated that p16 is technically simple immunohistological marker applicable for routine pathological histology.