Even though many hypotheses have been derived from the anatomical and functional analysis of in vivo models of brain tumors, it is still impossible to explain the mechanism of peritumoral edema. To determine whether increased permeability in a blood-brain barrier model correlated with the malignancy of a co-cultured brain tumor, the authors established an in vitro brain capillary endothelial monolayer co-culture model. Water-soluble factors which might explain the pathogenetic mechanism of peritumoral edema in brain tumors were expected and observed. The benign cell co-culture model used co-cultured astrocytoma cell lines such as C6 and H683 in the second compartment of a brain capillary endothelial monolayer culture model circumscribed with a 0.4u sized porous membrane which permitted communication of the media but limited cell migration to another compartment, and the malignant cell co-culture model used co-cultured glioblastoma cell lines such as 87MG and 373MG. Permeability at molecular weight 373 increased in the astrocytoma and glioblastoma co-culture models to 150% and 240% respectively, of that in a normal astrocyte co-culture model. Permeability at this molecular weight also increased in the astrocytoma- and glioblastoma-conditioned medium culture models to 38% and 131%, respectively, of that in a normal astrocytoma-conditioned medium culture model. The observed result was that permeability of the endothelial monolayer increased in accordance with the malignancy of co-cultured cells in the system permitting-other than cell migration-media transfer only. The result suggested that some factor soluble in media secreted from co-cultured cells changes the permeability of the endothelial monolayer and could explain the pathogenetic mechanism of peritumoral edema in malignant brain tumors.