The aim of the present study was to examine the clinical significance of lymph node metastatic (LNM) foci in predicting the overall survival of oral squamous cell carcinoma (OSCC) patients with LNM. MMP-21 was screened based on the LNM animal model of OSCC. Then four proteins, matrix metalloproteinase (MMP)-2, MMP-21, vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 were examined by immunohistochemistry in 63 OSCC specimens, including the primary tumors (PTs) and the corresponding LNM foci. The expression levels between the PTs and LNM foci were compared by Wilcoxon paired test. Relationships between expression of the four proteins and patient overall survival were assessed by Kaplan-Meier based on the median of the labeling index. The Cox proportional hazards model was used to assess the relative hazard factors. MMP-21 and VEGF-C expression levels were higher in the LNM foci than levels in the PTs. Results showed that MMP-2 and VEGF-C expression levels in the PTs and MMP-2, MMP-21 and VEGF-C expression in the LNM foci correlated with the overall survival of the OSCC patients with lymphatic metastasis. MMP-21 expression level in the LNM foci was the most reliable predictor among all the tested factors. These results suggest that high MMP-21 expression in LNM foci can be used to predict survival in OSCC patients with LNM. Characteristics of LNM foci may be more reliable than PT characteristics in predicting the overall survival of OSCC patients with lymphatic metastasis.