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Background: Neuroblastoma, one of the most prevalent infant malignancies, is heterogeneous and easily spreads into other organs causing life-threatening consequences. Different characters of organs (such as the germ layers where the organs derived from) exert different growth microenvironments and potentially influence the behavior of metastatic neuroblastoma cells and the prognosis of patients. However, limited information is been known about this in neuroblastoma. Objectives: To compare characteristics of neuroblastoma, primarily originating from the same germ layer (the seeds), in different tissues (microenvironment) derived from different germ layers. Methods: We performed retrospective analysis of SEER (Surveillance, Epidemiology, and End Results) data (1973-2014), patients with malignant neuroblastoma were grouped based on the primary lesion site (mesoderm-, ectoderm-or endoderm-derived tissue). Baseline demographic and clinical characteristics were compared between groups. Due to difficulties of processing incomplete SEER data, therapeutic method and survival rates were analyzed using cases from another SEER database (2000-2014). Results: The analysis included 3701 patients: 1970 (53.2%) in the mesoderm group, 1017 (27.5%) in the ectoderm group and 714 (19.3%) in the endoderm group. Tumor histology differed between groups (P < 0.01): the ectoderm group had mostly neuroblastoma (79.2%), as did the mesoderm group (71.1%), whereas the endoderm group contained mainly olfactory neuroblastoma (94.7%). The tumors (mean size: 69.14 ± 58.37 mm) were most commonly poorly differentiated with local extension, although lymph node invasion and distant metastasis occurred in a minority of cases. Compared with the other groups, the endoderm group had smaller (43.89 ± 20.84 mm) and better-differentiated tumors and a lower prevalence of lymph node invasion and metastasis (P < 0.05). Despite this, overall survival was poorest for the endoderm group (P < 0.05). Radiotherapy improved overall survival in the endoderm and ectoderm groups but worsened overall survival in the mesoderm group (P < 0.05). Conclusions: Malignant neuroblastoma characteristics may be influenced by the tumor microenvironment. In the youngest patients, decision-making regarding the best choice of therapy should be delayed until accurate risk stratification is possible.