BACKGROUND: Previously, we established an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC), including the human immortalized oral epithelia cells (HIOECs) and its derived cancerous HB cells. Then, expression microarray analysis showed that the gene encoding fos-related activator-1 (Fra-1) was significantly upregulated in the cancerous HB cells compared with HIOECs. METHODS: To confirm the expression of Fra-1 at mRNA and protein levels by real-time PCR and western blotting analysis in the carcinogenesis model of OSCC and CAL27 cells. To investigate Fra-1 expression in clinical samples from 30 primary OSCC patients by immunohistochemistry. RESULTS: Fra-1 expression was increased both at mRNA and protein levels in this carcinogenesis model of OSCC and CAL27 cells. Nuclear and cytoplasmic Fra-1 protein expressions both increased in the cancerous tissues compared with those in the paired adjacent non-malignant epithelia (nuclear: P < 0.001, cytoplasmic: P = 0.003). A higher level of nuclear Fra-1 expression was seen in the tumor samples of patients with lymph node metastasis than those without lymph node metastasis (5.07 +/- 1.33 vs 3.81 +/- 1.33, P = 0.023). Higher level of Fra-1 expression was also found in the tumor invasive margin than tumor center. CONCLUSIONS: Fra-1 is a positive gene of OSCC development and progression, Fra-1 can be used as a potential therapeutic target gene and an additional marker for evaluation of lymph node metastasis.