Neuroblastoma is a highly heterogeneous disease with a difficult prognostic prediction and non-uniform response to treatment. Hypoxia is an important driver of proliferation and development of resistance to chemotherapy in cancer cells. However, the prognostic significance of hypoxia-inducible genes expression in the neuroblastoma remains controversial. In this study, we aimed at scrutinizing the prognostic power of a broader group of protein-encoding genes associated with hypoxia response and testing these genes if can stratify neuroblastoma in different risk group. To test this hypothesis, the mRNA expression profiles, and corresponding clinical data from a cohort of 498 neuroblastoma patients were analyzed and further processed to compute a multigene transcriptional risk score. Our results showed that most of the hypoxia-related genes (71.21%) were differentially expressed between stage groups with lower and higher risks in the training cohort. 106 differentially expressed genes (DEGs) were significantly correlated with overall survival (OS) in the univariate Cox regression analysis. Further, a transcriptional signature of fifteen genes was summoned in a single risk score by lasso cox regression to stratify patients into two risk groups. Following this stratification, the patients in the high-risk group presented a significantly shorter OS compared to patients in the low-risk group. The prognostic capabilities of this score were further tested in other cohorts with similar results. In summary, our results indicate that hypoxia response genes have a prognostic value for high- and low-risk neuroblastomas. Furthermore, they can be aggregated into a single risk-score to predict neuroblastoma outcome.