The interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in interaction between immune and nervous system. Although IL-6 has neurotrophic properties and beneficial effects in the CNS, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. The source of the increase in peripheral IL-6 remains to be established and varies among different pathologies, but has been found to be associated with cognitive dysfunction in several pathologies. This comprehensive review provides an update summary of the studies performed in humans concerning the role of central and peripheral IL-6 in cognitive dysfunction in dementias and in other systemic diseases accompained by cognitive dysfuction such as cardiovascular, liver disease, Behçet's disease and systemic lupus erythematosus. Further research is needed to correlate specific deficits in IL-6 and its receptors in pathologies characterized by cognitive dysfunction and to understand how systemic IL-6 affects high cerebral function in order to open new directions in pharmacological treatments that modulate IL-6 signalling.