Purpose: Malignant pleural mesothelioma (MM), a rare tumor characterized by high local invasiveness and low metastatic efficiency, is poorly responsive to current therapeutic approaches. The aim of the present study was to evaluate the cytotoxic efficacy of the hybrid polar compound hexamethylene bisacetamide (HMBA), either as a single agent or in combination with the anthracycline doxorubicin (DOX), against MM cells. Methods: The MM cell lines MM-B1 and MM-E1 were treated with HMBA, DOX or with combinations of the two drugs. Cell survival and death were assessed by the MTS assay and trypan blue staining/TUNEL, respectively. The interactions between drugs were evaluated by the method of Kern et al. Western blot analysis was used to investigate the expression of Bcl-2 family proteins. Results: When administered alone, HMBA dose-dependently decreased the number of viable cells and increased the death rate of MM-B1 and MM-E1 cultures. Combinations of HMBA and DOX achieved a synergistic inhibition of MM cell survival, and the simultaneous administration of HMBA counteracted the resistance induced by DOX in MM-E1 cells. HMBA, used at cytostatic concentrations, reduced the ratio between antiapoptotic (Bcl-2, Bcl-X L) and proapoptotic (Bax) members of the Bcl-2 family of proteins, thus lowering the threshold for MM cell death commitment. Conclusions: HMBA has therapeutic potential in MM both as a single agent and through potentiation of DOX toxicity. These results support future investigations on the feasibility of intrapleural chemotherapy with this hybrid polar compound.