Signal regulatory protein $\alpha $ (SIRP$\alpha$) is a transmembrane protein that is commonly expressed in cells of the hematopoietic system and brain. Its function is not fully understood but it includes tumor suppressor properties and effects on differentiation. SIRP$\alpha $ may play a role in the development of medulloblastoma (MB), a WHO grade IV brain tumor, which is the most common malignant brain tumor in childhood. The aim of the current study was to determine the possible role of SIRP$\alpha $ in MB cells. Interestingly, in contrast to normal cerebellum, SIRP$\alpha $ mRNA was strongly downregulated in MB and its protein was not detectable in MB tissues. This down-regulation in MB cells was associated with transcriptional silencing of SIRP$\alpha $ via CpG island promoter hypermethylation. Furthermore, Oncomir cluster miR17-92 and miR-106a were correlated with SIRP$\alpha $ gene silencing in MB tumor specimens and cell lines. Histone modification and inhibition of DNA methylation using TSA (20 nM) for 24 hrs and 5-AZA (5 $\mu $M) and DZnep (2.5 $\mu $M) for 72 hrs, respectively, increased SIRP$\alpha $ expression 25-40 fold and resulted in 90% cytotoxicity of MB tumor cell lines D283-med and D458-med. Remarkably, forced upregulation of SIRP$\alpha $ by viral transduction in MB cell lines did not affect cell growth. In conclusion, SIRP$\alpha $ is epigenetically silenced in MB cells and tumor specimens by promoter hypermethylation and possibly by miRNA expression. SIRP$\alpha $ hypermethylation in MB might reflect the precursor cell state of these cells, rather than being a tumor-specific event, since SIRP$\alpha $ overexpression did not influence MB cell viability. The mechanism of the anti-MB action of epigenetic therapy requires further investigation since our findings indicate that this effect is independent of SIRP$\alpha $ upregulation.