The human Distal-less Homeobox (DLX) gene family encodes homeobox transcription factors involved in the control of morphogenesis and tissue homeostasis, which is primarily expressed in embryonic development. Recently, DLX gene family was reported to have essential roles in carcinogenesis. We have profiled whole genome expressed genes in 83 glioblastoma multiforme (GBM) patients from the Chinese Glioma Genome Atlas (CGGA) Group. Two major groups of samples were identified in mRNA expression profiles (referred to as Cluster 1 (C1) and Cluster 2 (C2)). We identified 7 out of the top 10 Gene Ontology terms in the C1 group were associated with differentiation and development of neuronal cell. The most significant prognostic gene was DLX2 (P < 0.001, OR = 1.744); overexpression of DLX2 indicated poor survival in the 83 GBM patients (low DLX2 vs high DLX2, 77.6 vs 44.7 weeks, P < 0.001). Annotation of mRNA profiling data on GBM from The Cancer Genome Atlas and MD Anderson Cancer Center showed the proneural and neural subtypes highly correlated with low and high DLX2 expression, respectively. Knocking down of DLX2 in GBM cell line-LN229 results in decreased cyclin D1 expression and cell proliferation. Collectively, these data identified high expression of DLX2 as a poor prognostic marker to GBM patients.