Medulloblastoma (MB), the most devastating and common brain tumor in children, is highly invasive and extremely difficult to treat. Identifying the properties of MB tumors that cause them to invade and metastasize is therefore imperative for the development of novel treatments. We performed investigations to elucidate prognostic implications of heparanase (HPSE-1) and TrkC/p75^NTR expression in MB using formalin-fixed, paraffin-embedded (FFPE) MB clinical specimens from children aged 1–19 years. Expressions of p75^NTR and HPSE-1 correlated with each other (Pearson’s correlation R = 0.899; P < 0.0001; R ² = 81%; n = 14). In addition, TrkC:p75^NTR ratios correlated with MB meningeal spread (R = 0.608; P = 0.0212; R ² = 37%; n = 14). Secondly, using antibodies specific to TrkC and HPSE-1, we carried out immunohistochemistry (IHC) on 22 human MB tissue samples. IHC reaction scores revealed a significant expression of HPSE-1 in 76% of MB tissues from children aged 3 years and older (P = 0.0490; n = 17) while TrkC immunoreactivity was detected in 71% of these patient samples. Of note, TrkC was significantly present in 100% of MB female patients (P = 0.0313; n = 6). These studies support the role of p75^NTR and HPSE-1 as two novel molecular determinants involved in the biology and clinical progression of MB.