There is not a consensus on the best therapeutic approach to mesothelioma and the prognosis is still dismal. We have recently demonstrated that HtrA1 is a potential therapeutic target in mesothelioma cells. In this manuscript we describe that electroporation in a mouse mesothelioma xenograft was able to facilitate the expression of exogenous HtrA1 injected intra-lesionally in the tumors and to increase the penetration in the neoplastic cells of cisplatin given intra-peritoneally. Indeed, HtrA1 over-expression caused a significant slowing down of tumor growth; moreover, cisplatin efficacy in reducing tumor mass was amplified by electroporation and this phenomenon was even more significant when combining the electroporation of cisplatin and HtrA1. Considering that a substantial number of mesothelioma patients develop early local recurrence, even with radical resection combined with aggressive chemo- and radiotherapy, this multi-modality approach could be very effective in improving local tumor control after surgery. The identification of effective combination coupled with the development of novel equipments and electrodes will be instrumental in planning the translation of these results to humans as per correct laboratory-clinical interface.