Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans, whose invasiveness and proliferation are associated with poor prognosis. Matrix metalloproteinases (MMPs) and the related family of "a disintegrin and metalloproteinase" (ADAM) both contribute to increase cell invasion, and its substrate N-cadherin is involved in proliferation and metastatic capacities of tumor cells. However, these molecular determinants of aggressiveness have not been adequately characterized in GBM. In an attempt to better define these pathogenetic signatures, in the present study we evaluated the comparative expression of two main MMPs (MMP-2 and -9), as well as of ADAM-10 and N-cadherin in surgical samples from patients diagnosed with WHO grade IV GBM (n = 25) and in cortical tissue specimens obtained from untreatable epileptic patients (controls, n = 8) through a series of histopathological, immunohistochemical and biochemical tests. Our studies revealed that both MMP-2 and -9 immunoreactivities (IRs) were upregulated in 13 of 25 (52 %) and 19 of 25 (76 %) GBMs, respectively, and the extent of the increase was highly significant with respect to controls (p < 0.001). ADAM-10 IR was also found to be increased (p < 0.001) in 16 of 25 GBM specimens (64 %). Conversely, N-cadherin IR was remarkably decreased (p < 0.001) in almost the totality of tumor samples (22 of 25, 88 %). A similar trend was also obtained at the mRNA and protein level by qPCR and western blot analyses, respectively. Collectively, the current study provides a comprehensive molecular portrayal of some of the major pathological hallmarks of GBM aggressiveness, which could be exploitable as potential targets for a new therapeutic approach.