Neuroblastoma (NB), an embryonal malignancy, poses a major challenge in pediatric oncology for the treatment of disseminated forms. Here, we report the decrease of Wnt-5a gene expression in high-risk NB (HR-NB) as well as in cultured metastatic neuroblasts. Wnt-5a is a member of the Wnt signaling pathway which is mainly associated with patterning decisions in the embryonic nervous system. Moreover, Wnt-5a has been involved in metastatic melanoma progression and invasive ductal breast cancer via adhesion and migration alterations. As retinoic acid (RA) plays a major role in the neural crest induction and differentiation, we showed that RA reverses the aberrant negative regulation of Wnt-5a in metastatic neuroblasts. While beta-catenin expression remained unchanged, PKC-theta, a protein kinase C isoform, was evidenced to increase and parallel Wnt-5a level. For the first time, the involvement of Wnt-5a through the Wnt/calcium signaling is highlighted in the pathogenesis of a pediatric embryonal malignancy, NB.