The tyrosine kinase c-Src plays an important role in the differentiation and survival of neuroblastoma (NB) cells, however the mechanism(s) activating this pathway remains poorly defined. Here, we characterize PAG1 (Cbp, Csk binding protein), an inhibitor of c-Src and other Src family kinases, as a novel tumor suppressor for neuroblastoma. Gene expression data from multiple independent NB clinical cohorts demonstrate that low expression of PAG1 is a significant prognostic factor for poor overall and event-free survival (p<0.0001), independent of MYCN status. Other disease factors, such as relapse or tumor progression, risk of death due to disease, high stage disease are also found to be inversely correlate with PAG1 expression (pPAG1 and MYCN expression levels (p<0.001) in all patient cohorts. PAG1 overexpression in NB cell lines significantly reduces proliferation and anchorage-independent colony formation in vitro with inhibition of pSRC, pAKT and pERK downstream of c-Src, while PAG1 Knockdown rescues these effects. Furthermore, PAG1 overexpression dramatically inhibits in vivo tumorigenicity of orthotopic xenografts (MYCN-amplified NGP (p=0.007) and non-amplified SH-SY5Y (p=0.001). The clinical data above and the lack of a canonical E-box site for MYCN binding at the PAG1 promoter, suggests this gene is indirectly repressed by MYCN possibly via microRNAs. Of note, the PAG1 3’ UTR contains target sites for mir-17-92, miR-34a, miR-26 and other MYCN regulated microRNAs implicated in MYCN mediated pathogenesis. These miRs also target additional targets down stream of Src as noted by Ingenuity analysis. Overall our data establish PAG1 as a potent tumor suppressor in neuroblastoma and suggest that reactivation of PAG1 and inhibition of c-Src kinase activity represents a novel therapeutic approach for high-risk neuroblastoma.