Aims: Novel missense mutations of the epidermal growth factor receptor (EGFR) extracellular domain have been recently described in a large series of glioblastomas.Methods: The exons 2, 3, 7, 8 and 15 coding for the EGFR extracellular domain were sequenced in a series of 161 consecutive primary glioblastomas and correlated with clinical features of patients in order to determine whether these alterations are linked to specific clinical characteristics of the disease.Results: Missense mutations were observed in 18 cases (11.2%), and 4 novel mutations were detected, including G178C, A271C, C818A and C1860G. Mutations of the EGFR extracellular domain were not associated with overall survival or with age at onset of the disease. In contrast, the EGFR extracellular domain mutations were significantly associated with patients' gender. Indeed, 15 mutations were observed in men vs. 3 in women (P < 0.05). EGFR extracellular domain mutations were also strongly associated with EGFR amplification (P < 0.0001).Conclusions: To our knowledge, EGFR extracellular domain mutations are the first genomic abnormalities associated with gender in primary glioblastomas, although a link between mutations of the EGFR tyrosine kinase domain and gender has been previously made in lung cancer.