BACKGROUND: Bortezomib, a specific and selective inhibitor of the 26S proteasome with antitumor activity against a wide range of malignancies, has been approved for the treatment of relapsed or refractory multiple myeloma and other cancers. Recently, bortezomib has been identified as an effective inhibitor of neuroblastoma cell growth and angiogenesis. RESULTS: In the present study, we demonstrate that some neuroblastoma cell lines are actually resistant to bortezomib. We have sought to characterize the main pathway by which proteasome inhibition leads to apoptosis, and to define the mechanism responsible for resistance to bortezomib in neuroblastoma cells. Our results show that SB202190, an inhibitor of mitogen-activated protein kinase (MAPK) p38, enhances the ability of bortezomib to induce apoptosis by preventing the phosphorylation of the heat shock protein (HSP) 27. CONCLUSION: This study opens the way to further clinical investigations and suggests a potential benefit of using a combination of bortezomib with an inhibitor of p38 MAPK for the treatment of neuroblastoma relapse.