Abstract The application of non-thermal atmospheric pressure plasma raises a hope for the new wound healing strategies. Next to its antibacterial effect it is known to stimulate skin cells. However, monocytes are also needed for the complex process of a wound healing. This study investigates the impact of plasma on the intracellular signaling events in the primary human monocytes. The proliferative MEK-ERK (MAPK/ERK kinase-extracellular signal-regulated kinase) pathway was activated by short plasma treatment times. In contrast, an induction of the apoptotic JNK (c-Jun N-terminal kinase) cascade as well as activation of caspase 3 were observed after long plasma exposure. These findings indicate that monocytes can be differentially stimulated by plasma treatment and may contribute to the proper wound recovery.