Tumor hypoxia is associated with resistance to radiotherapy and anticancer chemotherapy. However, it can be exploited to therapeutic advantage by concomitantly using hypoxic cytotoxins, such as tirapazamine (TPZ). Tumor electroporation offers the means to further increase tumor hypoxia by temporarily reducing tumor blood flow and therefore increase the cytotoxicity of TPZ. The primary objective of this work was to determine whether electric pulses combined with TPZ and radiotherapy (electroradiochemotherapy) was more efficacious than radiochemotherapy (TPZ + radiation). In these studies using the SCCVII tumor model in C3H mice, electroradiochemotherapy produced up to sixfold more tumor growth delay (TGD) than TPZ + radiation. In these studies, (1) large tumors (280 +/- 15 mm3) responded better to electroradiochemotherapy than small tumors (110 +/- 10 mm3), (2) TGD correlated linearly with tumor volume at the time of electroradiochemotherapy, (3) electric pulses induced a rapid but reversible reduction in O2 saturation, and (4) the electric field was highest near the periphery of the tumor in a 3D computer model. The findings suggested that electroradiochemotherapy gained its therapeutic advantage over TPZ + radiation by enhancing the cytotoxic action of TPZ through reduced tumor oxygenation. The greater antitumor effect achieved in large tumors may be related to tumor morphology and the electric-field distribution. These results suggest that electro-pulsation of large solid tumors may be of benefit to patients treated with radiation in combination with agents that kill hypoxic cells.