<p>Cold atmospheric pressure plasma (CAP) has emerged as a promising therapeutic modality in wound healing, with multiple devices now certified for clinical use. However, the constructive and functional diversity of CAP technologies poses significant challenges for cross-device comparison in preclinical in vitro studies. In this study, we evaluated how device-specific parameters and experimental conditions influence cytotoxic outcomes across different CAP technologies. Using L929, GM00637, and HaCaT cells, we compared direct treatment with a plasma jet (kINPen^® MED) and a surface micro-discharge device (plasma care^®), revealing significant differences in the reduction of metabolic activity under otherwise identical conditions. Assessment of treatment geometry—specifically the radius of circular motion of the plasma jet—significantly affects metabolic activity, even at identical exposure times. To standardize conditions across devices, we further investigated an indirect treatment approach using a metal grid to generate plasma-conditioned PBS. However, we found a non-linear relationship between liquid volume, treatment time, and biological outcome. Moreover, indirect treatment excludes short-lived reactive species and non-chemical plasma components, limiting its biological relevance. Our findings demonstrate that neither direct nor indirect treatment protocols reliably enable cross-device comparisons in vitro. We therefore advocate for transparent, comprehensive reporting of all device and experimental variables, rather than pursuing a single standardized protocol. This enables meaningful data integration and cross-study comparisons, even when protocols differ.</p>