When co-cultured with Pf-iRBC, we show evidence of key features involved in the pathogenesis of human cerebral malaria, including a decrease in TEER, increase in paracellular sodium fluorescein permeability, and disruption of ZO-1, occludin, and claudin-5 localization after 6 h of co-culture. Here, CLDN5 is linked to cerebral malaria.