Cold atmospheric plasma treatment acts at the cellular level to remove diseased tissue without inflammation and damage, to suppress infections and to modulate the viability (apoptosis/necrosis) of tumoral cells. It is also known that, a major cause of anti-tumor chemotherapy failure is the development of multidrug resistance (MDR) of tumors. This study reveals the effect of high voltage pulsed, repetitive cold atmospheric plasma jets which are chemically activated with oxygen, on B16 tumoral cells (murine melanoma cell line) and COLO320DM multidrug resistant cells (human colon cancer cell line). The tests have been performed on human colon cancer cell line COLO320DM and murine melanoma cell line B16-F10. These cell lines have been treated with cold helium or helium-oxygen generated plasma jets and the consequent apoptosis has been analyzed by means of flow cytometric method. A treatment time-dependent apoptosis has been observed only in the case of 816-F10 cells interacting with helium-oxygen plasma and no apoptosis has been identified when the cells were treated only with helium plasma jets. These results indicate the need of oxygen for the chemical activation of plasma. The COLO320DM cells (that over-express the MDR efflux pumps) have been exposed to helium-oxygen plasmas only, or in a combination with vegetal extract MCS D161 as MDR efflux pumps inhibitor. For the secondly mentioned case the results have showed an increased apoptosis rate compared to the plasma treatment alone. The obtained data represent a starting point for the study of a possible combined treatment (atmospheric pressure cold plasmas and a MDR efflux pumps inhibitor applied with chemotherapy).