Histopathological and immune-histochemical studies were carried out in four cases with multiple lacunes of the central grey matter and in control cases without such lesions. Routine light microscopic techniques were applied on paraffin-embedded material to identify lesions that may represent developing lacunes. In addition, polyclonal antisera to human albumin, IgG, fibrinogen and fibronectin were chosen as markers for extravasated plasma proteins. The brain tissue between lacunes contained several forms of focal injuries which may represent precursors of lacunes. Such lesions included foci of status spongiosus and status cribrosus, regions with dilated extracellular spaces and astrocytic gliosis, and multi-locular cysts. These "lacune-associated lesions" often included albumin immune-reactivity in extracellular spaces, nerve cell bodies and astrocytes. Less frequently signs of extravasated IgG, fibrinogen and fibronectin were identified. Thus, lacunes of the human brain frequently showed signs of antigenic sites to albumin. The extracellular deposits probably represent extravasated material from the blood. Vasogenic and cytotoxic oedema combined with other factors probably play important roles during the formation of some of the lacunes.