Thioredoxin reductase 1 (TrxR1) catalyzes the nicotinamide adenine dinucleotide phosphate-dependent reduction of oxidized thioredoxin (Trx). Trx, which is over-expressed in many human tumors, is a selenocysteine-containing protein associated with cell proliferation and apoptosis inhibition. This selenium-containing redox system regulates the activity of various enzymes and counteracts oxidative stress in cells such as hypoxia and cytotoxic agents. Consequently, TrxR1 could play an important role in tumor progression and resistance to chemotherapy due to its anti-apoptotic functions. To characterize cancer-related gene expression changes in oral squamous cell carcinomas (OSCC), we compared the gene expression profiles in OSCC primary tumors with patient-matched normal oral epithelium. Microarray analysis showed TrxR1 upregulation in primary tumors. Gene ontology analysis showed highly significant cancer-related function. The TrxR1 expression examined by immunohistochemistry was correlated with regional lymph node metastasis (P<0.05) and the clinical stages of 50 patients (P<0.01). Overexpression of TrxR1 could contribute to cancer progression and might be a potential molecular marker for therapy.