BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor in childhood with a 5-year survival of approximately 60%. We have recently shown that treatment of human MB cells with 5-aza-2'-deoxycytidine (5-aza-dC) reduces the clonogenic survival significantly. Here, we tested combinatorial effects of 5-aza-dC with other epigenetic (valproic acid, SAHA) and differentiation-inducing drugs (resveratrol, abacavir, retinoic acid) on human MB cells in vitro to intensify the antitumor therapy further. METHODS Three human MB cell lines were treated with 5-aza-dC alone or in combination for three or six days. Metabolic activity was measured by WST-1 assay. To determine long-term reproductive survival, clonogenic assays were performed. Induction of DNA double-strand break (DSB) repair was measured by γH2AX assay. RESULTS The applied single drugs, except for ATRA, reduced the metabolic activity dose-dependently in all MB cell lines. Longer treatment times enhanced the reduction of metabolic activity by 5-aza-dC. Combinatorial treatments showed differential, cell line-dependent responses indicating an important impact of the genetic background. 5-Aza-dC together with resveratrol was found to exert the most significant inhibitory effects on metabolic activity in all cell lines. 5-aza-dC alone reduced the clonogenicity of MB cells significantly and induced DSB with no further changes after adjuvant administration of resveratrol. CONCLUSION The observed significant decrease in metabolic activity by combinatorial treatment of MB cells with 5-aza-dC and resveratrol does not translate into long-term reproductive survival deficiency in vitro. Further studies in animal models are needed to clarify the resveratrol-mediated anticancer mechanisms in vivo.