Cyclin D1 overexpression and upregulation has been reported largely in Oral Squamous Cell Carcinoma (OSCC) but the mechanism behind it is not clear. Here, the transcription and translational upregulation of cyclin D1 was observed in most of the tobacco chewing oral cancer patients where as the gene amplification was limited to only small group (20%) of patients. A transcription factor (TF) binding site has been detected from -483 to -451 by using DNase I foot printing analysis and confirmed by electrophoretic mobility shift assay by using oral tumour nuclear extract (NE). This is a STAT binding sequence and confirmed as STAT 5a by super shift assay. The binding of STAT 5 was observed in 80% (24/30) oral cancer samples. The co-expression of cyclin D1 with STAT 5 binding was observed in 90% (27/30) of the samples. STAT family of proteins is emerging to play role in oral carcinogenesis. Here, the binding of STAT 5 might up regulate cyclin D1 in most of the samples whereas; the gene amplification events are sporadic in oral carcinogenesis. Our study provides the first evidence of the constitutive activation of STAT 5-cyclin D1 pathway in chewing tobacco mediated OSCC.