miR-129-2 is frequently downregulated in multiple cancers. However, how it is silenced in cancers remainsunclear. Here we investigated the expression profile and potential biological function of miR-129-2 in glioblastoma(GBM), the most common and lethal form of brain tumors in adults. We showed that miR-129-2 is lost inGBM patient specimens and cultured cell lines. miR-129-2 expression could be restored upon treatment witha histone deadetylase inhibitor (trichostatin A) but not a DNA methylation inhibitor (5-Aza-2’-deoxycytidine),and more profound effect was observed with the treatment of these two drugs in combination. Furthermore,forced expression of miR-129-2 repressed the expression of major oncogenic genes such as PDGFRa and Foxp1in GBMs. Consistently, expression of miR-129-2 significantly inhibits GBM cell proliferation in vitro. Theseresults reveal that miR-129-2 is epigenetically regulated and functions as a tumor suppressor gene in GBMs,suggesting it may serve as a potential therapeutic target for GBM treatment.