The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) has been implicated in cancer invasion and metastasis. This activity is known to be regulated by several inhibitors such as plasminogen activator inhibitors (PAIs). To elucidate the participation of the uPA system in the malignant behaviour of squamous cell carcinoma (SCC) in the oral cavity, uPA, uPAR, PAI-1 and -2 expression and localisation in 34 primary oral cancers were examined immunohistochemically. The results were then compared with clinicopathological findings. The positive rates of uPA, uPAR, PAI-1 and -2 expression were 23.5, 29.4, 29.4 and 11.8%, respectively. uPA expression correlated with mode of cancer invasion according to Yamamoto-Kohama's criteria (p < 0.01) and with secondary regional lymph node metastasis. uPAR expression also correlated with mode of invasion. In particular, the tumours of both uPA- and uPAR-positive [uPA(+)/uPAR(+)] cases were highly invasive. In the present study, neither PAI-1 nor PAI-2 expression correlated with clinicopathological parameters. However, PAI-2 negative cases of uPA(+)/uPAR(+) were significantly more invasive (p < 0.0001). Such uPA(+)/uPAR(+)/PAI-2(-) cases almost always showed secondary lymph node metastasis (p < 0.01). These results indicate that the uPA system plays a significant role in the invasive and metastatic processes of oral SCC, and that this system may be a powerful aid in evaluating the clinical course or prognosis of patients with oral cancer.