Our previous study using proteomic profiling demonstrated significant up-regulation of Septin1, a conserved family of GTPase proteins, in oral squamous-cell carcinoma (OSCC)-derived cell lines. In the current study, to determine the potential involvement of Septin1 in oral carcinogenesis, we evaluated the state of septin1 protein/mRNA expression in OSCC-derived cell lines, oral premalignant lesions (OPLs), and primary OSCCs. A significant (P<0.05) increase in Septin1 expression was evident in all OSCC-derived cell lines examined compared to human normal oral keratinocytes (HNOKs) and OPLs. In immunohistochemistry, while the vast majority of the OSCCs (89%) were positive for Septin1, no immunoreaction was observed in corresponding normal tissues and OPLs. In addition, real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) data were consistent with the protein expression status. These results suggest that Septin1 expression could contribute to cancer progression, proliferation, or both, and that Septin1 may be a potential diagnostic marker of highly active cancer and a therapeutic target for OSCCs.