Neovascularization plays a critical role in cancer metastasis. However, the molecular mechanism regulating the neovascularization in oral squamous cell carcinoma (OSCC) is poorly understood. Placental growth factor (PLGF) has been known to regulate pathological angiogenesis and has been recently shown to regulate matrix metalloproteinases (MMPs) for extracellular matrix degradation during neovascularization. Here we aimed to examine whether PLGF may regulate MMPs in the metastasis of OSCC. We found that PLGF and MMP9 levels strongly correlated in OSCC in the patients, both increased in the OSCC from the patients with metastasis of the primary OSCC. Thus, we used several human OSCC cell lines to examine the relationship between PLGF and MMP9. We found that overexpression of PLGF in OSCC cells increased expression of MMP9, while inhibition of PLGF in OSCC cells decreased expression of MMP9. However, adaptation of MMP9 levels in OSCC cells did not affect the levels of PLGF. These data suggest that PLGF may regulate MMP9 in OSCC cells, but not vice versa. Moreover, inhibition of ERK1/2, but not inhibition of PI3k or JNK pathways, substantially abolished the effect of PLGF on MMP9, suggesting that PLGF may increase expression of MMP9 via ERK/MAPK signaling pathway. Thus, our data demonstrate that PLGF-induced cancer neovascularization may be partially mediated through its effect on MMP9 activation in OSCC.