The exposure of aqueous solutions to atmospheric plasmas results in the generation of relatively long-lived secondary products such as hydrogen peroxide which are biologically active and have demonstrated anti-microbial and cytotoxic activity. The use of plasma-activated solutions in applications such as microbial decontamination or anti-cancer treatments requires not only adequate performance on target cells but also a safe operating window regarding the impact on surrounding tissues. Furthermore the generation of plasma-activated fluids needs to be considered as a by-stander effect of subjecting tissue to plasma discharges. Cytotoxicity and mutagenicity assays using mammalian cell lines were used to elucidate the effects of solutions treated with di-electric barrier discharge atmospheric cold plasma. Plasma-treated PBS inhibited cell growth in a treatment time-dependent manner showing a linear correlation to the solutions’ peroxide concentration which remained stable over several weeks. Plasma-treated foetal bovine serum (FBS) acting as a model for complex bio-fluids showed not only cytotoxic effects but also exhibited increased mutagenic potential as determined using the mammalian HPRT assay. Further studies are warranted to determine the nature, causes and effects of the cyto- and genotoxic potential of solutions exposed to plasma discharges to ensure long-term safety of novel plasma applications in medicine and healthcare.