Objective: To investigate the expression of vascular endothelial growth factor C (VEGF-C) and its receptor Flt-4 in human tongue squamous cell carcinoma (TSCC) and to elucidate their role in lymph node (LN) metastasis and other clinical significance. Methods: The expression of VEGF-C and Flt-4 was examined in 22 human TSCC biopsy specimens by reverse transcription-polymerase chain reaction (RT-PCR) and 55 human TSCC surgical specimens by immunohistochemistry. Results: VEGF-C mRNA was detected in 16 (72.7%) of the 22 fresh TSCC specimens, which was higher than that in the normal mucosa. In the 16 VEGF-C mRNA positive cases, 12 were positive for Flt-4 mRNA, and there was significant relationship between VEGF-C and Flt-4 in the cytoplasm of tumor cells. In the 55 surgical specimens of TSCC, 29 (52.7%) were VEGF-C positive in the cytoplasm of tumor cells. Flt-4 was mainly expressed in the lymphatic endothelial cells. Normal tissue exhibited no or weak VEGF-C. VEGF-C expression correlated with grade of tumor pathology and LN metastasis. On the other hand, correlation had no relationship to gender and age of the patients and tumor, nodes, metastasis (TNM) grade. Conclusion: The results overall suggest that VEGF-C/Flt-4 may play an important role in the LN metastasis and it could be a useful biological marker to foresee the cervical LN metastasis and prognosis.