We report on multi-level atomistic simulations for the interaction of reactive oxygen species (ROS) with the head groups of the phospholipid bilayer, and the subsequent effect of head group and lipid tail oxidation on the structural and dynamic properties of the cell membrane. Our simulations are validated by experiments using a cold atmospheric plasma as external ROS source. We found that plasma treatment leads to a slight initial rise in membrane rigidity, followed by a strong and persistent increase in fluidity, indicating a drop in lipid order. The latter is also revealed by our simulations. This study is important for cancer treatment by therapies producing (extracellular) ROS, such as plasma treatment. These ROS will interact with the cell membrane, first oxidizing the head groups, followed by the lipid tails. A drop in lipid order might allow them to penetrate into the cell interior (e.g., through pores created due to oxidation of the lipid tails) and cause intracellular oxidative damage, eventually leading to cell death. This work in general elucidates the underlying mechanisms of ROS interaction with the cell membrane at the atomic level.In recent years, cold atmospheric plasmas (CAPs) are gaining increasing interest for cancer treatment, i.e., so-called "plasma oncology" [1][2][3][4] . In a recent review, Schlegel et al. 1 summarize the results of several studies on plasma oncology and show the progress in the potential use of CAPs to effectively kill cancer cells (either by apoptosis or necrosis), in vitro as well as in vivo. CAP sources seem to be a powerful tool for cancer treatment, either alone or in combination with other conventional therapies. Indeed, recent experimental results showed that CAPs could enhance the effects of conventional chemotherapy even in resistant tumorous cells; the resistant cell population, if pre-treated with CAP, becomes sensitive to treatment with chemotherapy 5,6 . Moreover, it was demonstrated that plasma treatment, both in vitro and in vivo, is able to attack a wide range of cancer cell lines without damaging their normal counterparts 1, 2 . Thus, preliminary results seem very promising. Nevertheless, the application of CAPs for cancer treatment is still in its initial stage, and there is an enormous need for a better understanding of the underlying mechanisms.CAPs generate reactive oxygen species (ROS, e.g., OH, HO 2 , H 2 O 2 ) and reactive nitrogen species (RNS, e.g., NO, NO 2 , ONOO â ), which are generally believed to play a key role in plasma treatment 3,4,7 . Several studies showed that CAPs elevate intracellular ROS levels, thereby inducing oxidative damage in cancer cells, which can lead to cell death, i.e., apoptosis 3,8 . Normal cells, on the other hand, are able to defend themselves from this harmful effect of ROS by activating multiple anti-oxidative systems that reduce the increased oxidative stress and restore the balance 9, 10 . Besides, also the RNS generated by CAP might play an important role in cancer therapy (see ref. 4 and references therein). ...