Epidermal growth factor module-containing mucin-like hormone receptor-3 (EMR-3) is a G-protein coupled receptor with unknown ligand and cellular function. Upregulation of EMR-3 in glioblastoma (GBM) multiforme is associated with poor survival. We investigated the expression patterns and functional significance of EMR-3 in GBM using immunohistochemistry, western blot, reverse transcription PCR, and small interfering RNA knockdown in proliferation and invasion assays. EMR-3 is variably expressed in primary human GBM tissues and cell lines. Knocking down EMR-3 has no impact on cellular proliferation, but decreases cellular invasion by greater than 3-fold. EMR-3 is a potential mediator of cellular invasion in GBM. Given the poor survival associated with high levels of EMR-3 expression in glioma patients, our results provide impetus to explore EMR-3 as a potential therapeutic target.