In light of recent epidemiological studies that associate diabetes mellitus with increased risk for oral cancer, we investigated in diabetic (type I) and normal rats with induced oral squamous cell carcinoma whether the molecular basis for that putative association involves insulin receptor substrate-1 (IRS-1) and focal adhesion kinase (FAK). Fourteen diabetic and 12 normal rats developed cancer after 4-nitroquinoline-N-oxide treatment, while six diabetic and six normal animals were used as controls. Oral sections were studied using monoclonal antibodies against IRS-1 and FAK proteins. Expression of IRS-1 was significantly higher in diabetic than normal rats, but it decreased in diabetic animals with tumor, especially in more advanced stages. FAK expression was significantly higher in rats with cancer in comparison to the ones without it, regardless the diabetes status. These data suggest that the IRS-1/FAK pathway is altered by diabetes resulting in reduced cell adhesion and possibly increasing risk for oral cancer.