BACKGROUND/AIM: This proof-of-concept study evaluated the antitumor impact of a direct electrical stimulation technique, termed intratumoral modulation therapy (IMT) on glioblastoma (GBM) cells. MATERIALS AND METHODS: An in vitro IMT model comprised of a calibrated electrode to deliver continuous, low-intensity stimulation within GBM preparations. Viability and apoptosis assays were performed in treated immortalized and patient-derived GBM cells, and post-mitotic neurons. IMT was delivered alone and with temozolomide, or gene silencing of the tumor-promoting chaperone, heat-shock protein 27 (HSP27). RESULTS: GBM cells, but not neurons, exhibited >40% loss of viability, caspase-3 activation and apoptosis with IMT. Cell death was modest with temozolomide alone (30%) but increased significantly with concomitant IMT (70%). HSP27 silencing alone produced 30% viability loss, with significant enhancement of target knockdown and GBM cell death (65%), when combined with IMT. CONCLUSION: These findings warrant further evaluation of IMT as a potential novel therapeutic strategy for GBM.