It has long been recognized that spinal meningiomas show particular clinical and histological features. Here, we compare the clinico-biological characteristics as well as the genetic abnormalities and patterns of gene expression of spinal and intracranial meningiomas. Fourteen spinal and 141 intracranial meningioma patients were analyzed at diagnosis. In all tumors, interphase fluorescence in situ hybridization (iFISH) studies were performed for the detection of quantitative abnormalities for 11 different chromosomes. Additionally, microarray analyses were performed on a subgroup of 18 histologically benign meningiomas (7 spinal and 11 intracranial). Upon comparison with intracranial tumors, spinal meningiomas showed a marked predominance of psammomatous and transitional tumors (p = 0.001), together with a higher proportion of cases displaying a single tumor cell clone by iFISH (p = 0.004). In 86% of the spinal versus 56% of the intracranial tumors (p = 0.01), the ancestral tumor cell clone detected showed either absence of any chromosomal abnormality or monosomy 22/22q-alone. Analysis of gene expression profiles showed differential expression between spinal and intracranial meningiomas for a total of 1555 genes, 35 of which allowed a clear distinction between both tumor types. Most of these 35 genes (n = 30) showed significantly higher expression among spinal tumors and corresponded to genes involved in signal transduction pathways, which did not show a significantly different expression according to tumor histopathology. In summary, we show the occurrence of unique patterns of genetic abnormalities and gene expression profiles in spinal as compared to intracranial meningiomas that provide new insights into the molecular pathways involved in the tumorigenesis and progression of spinal meningiomas, and could help explain their particular clinical and histological features.