IL-18 is an important regulator in both innate and acquired immune responses. The aberrant expression of IL-18 is associated with severe inflammatory conditions, such as autoimmune diseases and allergies. Thus, human antibodies with inhibitory activity on IL-18 signaling may be useful for therapeutic applications. We report here the first establishment of an antagonistic anti-IL-18 complete human antibody, h18-108, employing a human single chain antibody (scFv)-displaying phage library. The h18-108 scFv inhibited the IFN-gamma production of a human myelomonocytic cell line, KG-1. Flow cytometry analysis showed that h18-108 blocked the binding of IL-18 to KG-1 cells. Epitope mapping analysis using two kinds of random peptide-displaying phage libraries and an IL-18 alanine mutant (D98A) demonstrated that the h18-108 scFv binds to the site 3 of IL-18, which is suggested to be an association site with the IL-18 receptor beta. The complete human Fab and IgG forms of h18-108 have been successfully constructed to attain increases in both binding affinity and inhibitory activity.