Salivary adenoid cystic carcinoma (SACC) is a frequent subtype of salivary gland malignancy, and it has an important biological behavior for perineural invasion (PNI). Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that is involved in the invasive property of many malignancies by stimulating matrix metalloproteinase (MMP) expression. The present study was designed to investigate the role and possible mechanism of EMMPRIN in the PNI of SACC using RNA interference (RNAi) technology. We found that silencing of EMMPRIN expression in the human SACC cell line (SACC-83) suppressed the cell proliferation, adhesion, MMP-2 and MMP-9 secretion, and PNI activity in vitro. EMMPRIN silencing also inhibited the tumor growth and Ki-67 labeled proliferation index in vivo. Using tumor PNI models in nude mice, EMMPRIN silencing inhibited the infiltration, swelling and functional loss of the affected sciatic nerves, as well as the expression of MMP-2 and MMP-9. These results demonstrate that EMMPRIN participates in the PNI of SACC cells by mediating the expression of MMP-2 and MMP-9. Our findings suggest that EMMPRIN is a potential target for anti-PNI treatment in SACC.