Glioblastoma multiforme (GBM) can arise de novo or progress from a lower to higher grade and can possess a series of genetic alterations and dynamic progressions, which have been correlated with the molecular pathology of GBM. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in a variety of tumors and is one of the important mediators responsible for the development of high-grade gliomas, especially in primary glioblastomas. Most recently, RNA interference (RNAi), in which double-stranded RNA (dsRNA) induces sequence-specific degradation of the targeting messenger RNA (mRNA), has been extensively developed and studied. RNAi is able to silence the targeted gene expression more efficiently and specifically. In the present study, we silence the EGFR expression using two separate short interfering RNAs (siRNAs) targeting the extracellular ligand-binding domain and intracellular tyrosine kinase domain, respectively. We demonstrate that suppression of EGFR expression, by using either antisense or siRNA approaches, inhibits U251 glioblastoma cell growth in vitro and in vivo, and siRNA seems to be more effective than the antisense approach.