The study aimed to clarify the role of electric pulses in combination with chemotherapy on the viability of keratinocyte cell line HaCaT, in the context of its application as a new therapeutic approach for psoriasis. The data show that electroporation of HaCaT cells in combination with rifampicin induces cytoskeleton disruption and increases permeability of cell monolayer due to cell-cell junctions' interruption, visualized by fluorescent imaging of E-cadherin and actin integrity. This was accompanied with synergistic reduction of cell viability. The study proposes a new opportunity for more effective skin treatment than chemotherapy. The future application of this electrochemotherapeutic approach for combined local treatment of psoriasis may have serous benefits because of a high possibility to avoid side-effects of conventional chemotherapy.