Squamous cell carcinoma of the oral cavity is one of the most common neoplasms in the world which arises from oral mucosal lining that accounts for over 90% of all these tumors.There are several etiological factors of oral cancer including tobacco use, betel-nut use, alcohol consumption, a diet poor in fresh fruit and vegetables, infective agents (Candida, viruses), immune deficiency and exposure to sunlight in case of lip carcinoma .p27Kip1 is a member of a family of cyclin dependent kinase (CDK) inhibitors that bind to cyclin/CDK complexes and arrest cell division. There is considerable evidence that p27Kip1 plays an important role in multiple fundamental cellular processes, including cell proliferation, cell differentiation, and apoptosis.This study was performed to investigate the immunohistochemical expression of p27kip1in OSCC and to correlate this expression with different grades in order to evaluate its role in progression.Five, normal control cases where selected from paraffin blocks of mesenchymal where the normal surface epithelium was considered the normal control. Thirty cases of paraffin blocks were investigated in the study were 14 specimens well differentiated, 7 specimens moderately differentiated and 9 specimens were poorly differentiated OSCC.From all the paraffin blocks, tissue sections were cut and stained with haematoxylin and eosin stains (H&E), re-diagnosed to confirm the previously made diagnosis, classified according to WHO criteria (Pindborg et al., 1997). Other sections were cut and placed on positively charged slides (optiplus) ready for immunostaining procedures.To assess of positive nuclei of the immunostaining, sections were examined with (magnification x200) Olympus CX21 microscope connected to a camera and computer. All the stained sections were examined by image analyzer computer system using the Image J software (v1. 46a, NIH, USA) that is capable of performing high speed digital image processing for the purpose of tissue measurements.Statistical analysis comparison between normal tissue and different grades of squamous cell carcinoma was carried out by analysis of Variance (ANOVA test), followed by Tukey’s post-hoc test. The statistical analysis revealed comparison between normal tissue and each grade of squamous cell carcinoma the greatest mean value of positive nuclear p27kip1 staining was recorded in the well-differentiated SCC (62.2±5.36), followed by the moderately-differentiated SCC (58±1.825), then the poorly-differentiated SCC (22.5±2.38). The lowest value was recorded in the normal tissue (2±1). Analysis of variance (ANOVA) test revealed that the difference between normal oral mucosa and each of the different grades of SCC was extremely statistically significant (<0.0001).Our results revealed positive p27kip1 expression in all studied cases with variables degrees of immunoreactivity. In the cases of well differentiated OSCC, the expression was detected as nuclear staining in addition to cytoplasmic immunoreaction in few malignant cells. Moreover, in moderately differentiated tumors some cytoplasmic reaction in the malignant cells where poorly differentiated showed mainly cytoplasmic.It was concluded that p27kip1immunoexpression could be related to differentiation and the progression of oral cancer. p27kip1 can be used as biomarker for prognostic purposes.