Neuroblastoma (NB) is a challenging problem in oncology, as the majority of patients have lymphatic and/or hematogenous metastases at diagnosis. We investigated the prognostic significance of lymphatic density (LD) and invasion (LI) in NBs using the lymphatic endothelial marker podoplanin (PDPN). A total of 77 neuroblastic tumors and 9 ganglioneuromas (GNs) were immunostained for PDPN using D2-40 antibody. Intratumoral lymphatics were identified in 87% (67/77) of NBs and 7/9 GNs. The LD counts were significantly higher (P<0.01) in NBs (median=19.6, range=0.00 to 89.3) than in GNs (median=10.2, range=0 to 18.7). LI, assessed in D2-40-stained lymphatics, was present in 52/67 (78%) NBs. LDs were significantly higher in NBs from patients with adverse clinical factors (advanced-stage, high-risk group, primary abdominal compared with extra-abdominal sites), biological factors (MYCN amplification, 1p deletion, 17q gain), and distant lymph node metastases. LDs and LI were also significantly higher in NBs belonging to an unfavorable pathology prognostic group and in those with a high mitosis-karyorrhexis index. High LD and the presence of LI correlated with a shorter event-free survival in univariable analyses. High LD and the presence of LI were also associated with worse overall survival, although the association was less strong. In conclusion, increased LDs and the presence of LI correlated with adverse clinicopathologic and biological factors and survival. These findings suggest that PDPN has the potential to provide valuable prognostic information to clinicians for risk assessment in NBs.