The epidermal growth factor receptor (EGFR) is commonly amplified and mutated in glioblastoma, making it a compelling therapeutic target. Recent reports have demonstrated clinical activity of the EGFR inhibitors gefitinib and erlotinib in a subset of glioblastoma patients. Co-expression of EGFRvIII, a constitutively active mutant receptor expressed in 50% of tumours, and PTEN, an inhibitor of PI3K activity, by glioblastoma cells is associated with clinical response to these EGFR kinase inhibitors. PTEN loss and resulting increased PI3K pathway activity appears to act as a resistance factor. A critical therapeutic challenge is to identify agents that enhance the anti-cancer effects of these agents and promote responsiveness to EGFR kinase inhibitors in a broader spectrum of glioblastoma patients. For example, combining gefitinib with inhibitors of the PI3K/AKT pathway show enhanced cytotoxicity in glioblastoma derived cell lines. Here, we show that targeting HMG-CoA reductase with lovastatin, that can affect the activity of multiple cell signaling pathways, significantly enhanced the sensitivity of glioblastoma cells to the EGFR kinase inhibitor gefitinib in the five cell lines tested. In an isogenic model system, U87MG glioblastoma cells expressing EGFRvIII and PTEN in relevant combinations, we show that combined gefitinib and lovastatin treatments induce potent synergistic cytotoxicity irrespective of EGFRvIII and PTEN status. These studies demonstrate the potential of lovastatin to augment the cytotoxic effects of gefitinib and provide a rationale for combined statin/EGFR targeted therapies in glioblastoma patients.