Stroke is a major cause of morbidity and mortality, and activation of the immune system can impact on stroke outcome. Although the majority of research has focused on the role of the immune system after stroke there is increasing evidence to suggest that inflammation and immune activation prior to brain injury can influence stroke risk and outcome. With the high prevalence of co-morbidities in the Western world such as obesity, hypertension and diabetes, pre-existing chronic ‘low-grade’ systemic inflammation has become a customary characteristic of stroke pathophysiology that needs to be considered in the search for new therapies. The importance of the immune system in stroke has been demonstrated in a number of ways, both experimentally and in the clinical setting. This review will focus on the effect of immune activation arising from systemic inflammatory conditions and infection, how it affects the incidence and outcomes of stroke, and the possible underlying mechanisms involved. This article is part of a Special Issue entitled ‘Neuroinflammation in neurodegeneration and neurodysfunction’.