Meningiomas (MGs) are frequent tumors of the CNS originating from the meningeal layers of the spinal cord and the brain. In this study, comparative tissue proteomic analysis of low and high grades of MGs was performed by using iTRAQ-based quantitative proteomics in combination with ESI-quadrupole-TOF and Q-Exactive MS, and results were validated by employing ELISA. Combining the results obtained from two MS platforms, we were able to identify overall 4308 proteins (1% false discover rate), among which 2367 exhibited differential expression (more than and equal to 2 peptide and ≥1.5-fold in at least one grade) in MGs. Several differentially expressed proteins were found to be associated with diverse signaling pathways, including integrin, Wnt, Ras, epidermal growth factor receptor, and FGR signaling. Proteins, such as vinculin or histones, which act as the signaling activators to initiate multiple signaling pathways, were found to be upregulated in MGs. Quite a few candidates, such as protein S-100A6, aldehyde dehydrogenase mitochondrial, AHNAK, cytoskeleton-associated protein 4, and caveolin, showed sequential increase in low- and high-grade MGs, whereas differential expressions of collagen alpha-1 (VI), protein S100-A9, 14 kDa phosphohistidine phosphatase, or transgelin-2 were found to be grade specific. Our findings provide new insights regarding the association of various signal transduction pathways in MG pathogenesis and may introduce new opportunities for the early detection and prognosis of MGs. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.