Amplification and mutation of the epidermal growth factor receptor (EGFR) are common features of malignant gliomas. The most frequent mutation seen in these tumors involves deletion of exon 2-7 resulting in a constitutively active form of the receptor (EGFRvIII, or deltaEGFR). Since EGFRvIII is found primarily in gliomas and has not been reported in sarcomas, we compared the effects of this altered receptor in immortalized primary astrocytes and fibroblasts. While EGFRvIII displayed ligand-independent autophosphorylation in both cell types, downstream signaling differed. While EGFRvIII increased the proliferative capacity of both astrocytes and fibroblasts consistent with activation of ERK in these cells, EGFRvIII activated AKT only in the immortalized astrocytes. EGFRvIII expression in astrocytes also led to increased radioresistance in that cell type. Furthermore, specific inhibition of phosphotidylinositol-3 kinase (PI-3K) with LY294002 reverted the radioresistant phenotype in the immortalized astrocytes. Thus, selective activation of PI-3K/AKT in astrocytes expressing EGFRvIII appears to be responsible for the observed increase in radioresistance. EGFRvIII's differential ability to activate the PI-3K downstream signal may explain why this mutant receptor is such a prominent lesion in malignant gliomas but less often seen in other tumor types, even those where EGFR signaling has a prominent role.