Abstract Vascular leakage and shock are the major causes of death in patients with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). It has been suggested that patients with an elevated level of the free soluble form of dengue virus (DV) nonstructural protein 1 (sNS1) are at risk of developing DHF. To understand the role of sNS1 in blood, we searched for the host molecule with which NS1 interacts in human plasma by affinity purification using a GST-fused NS1. Complement inhibitory factor clusterin (Clu), which naturally inhibits the formation of terminal complement complex (TCC), was identified by mass spectrometry. A recombinant sNS1 produced from 293T cells and sNS1 from DV-infected Vero cells interacted with human Clu. Since an activated complement system reportedly causes vascular leakage, the interaction between sNS1 and Clu may contribute to the progression of DHF.