Abstract: Brain injury is a major determinant of outcomes in patients after out of hospital cardiac arrest (OHCA). Because neuronal damage shows a typical, delayed course, it has been deducted that components of post–cardiac arrest neuronal injury are potentially treatable. However, considerable gaps in knowledge exist on the mechanisms that mediate neuronal injury in this setting. Mast cells (MCs) are perivascular immune sentinel cells best known to trigger acute inflammation and shock in allergic responses. Supported by our preliminary findings, we hypothesize that MCs are also central effectors in development of neuro-inflammation and neuronal injury after OHCA. As such, we documented robust MC activation after cardiac arrest in both a mouse model and in recovering patients. Furthermore, MC-deficient mice displayed reduced disruption of their blood brain barrier and less infiltration of inflammatory cells indicating that they may be protected from harmful secondary responses after cardiac arrest. Consequently, the objective of our work is to establish several independent lines of research in mice and in patients in order to comprehensively characterize the MC contribution to neuroinflammation and neuronal injury following cardiac arrest. This project constitutes a crucial step towards our long-term goal to establish MCs as key cellular targets of the harmful responses to cardiac arrest and to develop novel therapeutic and diagnostic tools that improve the care of these critically ill patients.