The interaction between the brain and immune system has been intensely studied in patients with several central nervous system (CNS) disorders including brain trauma and brain tumours. Pioneering studies described cellular immune changes after human stroke more than three decades ago but the potential existence of a CNS- mediated immunodepression syndrome has obtained renewed attention only recently. The CNS and the immune system are extensively interconnected through neural pathways, hormonal cascades and cell-to-cell interactions orchestrated primarily by cytokines. Indeed, the balance between pro- and anti-inflammatory cytokines determines the prowess of the immunological response but could also influence the fate of the injured brain tissue and the threshold to develop complications including systemic infection. Prominent changes in primary and secondary lymphoid organs and increased susceptibility to infections and pneumonia have been described in a mouse model of transient focal cerebral ischemia in support of the existence of a stroke induced immunodepression syndrome. Yet, the intrinsic characteristics of secondary lymphoid organs located in areas that receive direct signals from the CNS could mediate anti-inflammatory responses after stroke. In human stroke, the balance between pro-inflammatory and anti-inflammatory cytokines is an important prognostic clinical factor. Recent data also suggest that the appearance infections early after stroke could be the manifestation of a stroke-induced immunodepression syndrome, characterized by strong adrenergic activity and excessive anti-inflammatory drive. Overall, current research suggests that a better understanding of the reciprocal effects between the CNS and the immune system could pave the way to more effective therapies for this devastating condition.