Abstract: Objective To study the expressions of PTEN, FHIT and cyclin D1 in normal oral mucosa and oral squamous cell carcinoma (OSCC), and analyze the relationship between PTEN/FHIT and cyclin D1. Methods Immunohistochemical staining with SP methods was used to detect the expression of PTEN, FHIT and cyclin D1 in OSCC tissues in 62 cases and normal oral mucosa in 12 cases. Results The positivity rates of PTEN and FHIT were both 100% (12/12) in the normal oral mucosa, while in 62 cases of OSCC, 24.2% (15/62) and 17.7% (11/62) were negative for (or with low expression of) PTEN and FHIT, respectively. In normal oral mucosa, 91.7% (11/12) cases had negative or low cyclin D1 expression, while 53.2% (33/62) of the OSCC cases were positive for cyclin D1 expression. In all the cases, when PTEN and FHIT were strongly expressed, 37.8% (28/74) of the cases had negative or low expression of cyclin D1, including 11 normal cases. Conclusion The tumor suppressor genes PTEN and FHIT play a role in the pathogenesis of OSCC, and PTEN and FHIT can down-regulate the expression of cyclin D1.