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Dengue virus ( DENV) infection is an arthropod-borne disease with increasing prevalence worldwide. Attempts have been made to develop therapeutic molecules for treatment for DENV infection. However, most of potentially therapeutic DENV monoclonal antibody was originated from mouse, which could cause undesirable effects in human recipients. Thus, fully human antibody is preferable for therapeutic development. Human single-chain variable fragments ( Hu Sc Fv) with inhibitory effect to DENV infection were generated in this study. Hu Sc Fv molecules were screened and selected from the human antibody phage display library by using purified recombinant DENV full-length envelope ( FL- E) and its domain III ( EDIII) proteins as target antigens for biopanning. Hu Sc Fv molecules were then tested for their bindings to DENV particles by indirect ELISA and immunofluorescent microscopy. EDIII-specific Hu Sc Fv exhibited neutralizing effect to DENV infection in Vero cells in a dose-dependent manner as determined by plaque formation and cell ELISA. Epitope mapping and molecular docking results concordantly revealed interaction of Hu Sc Fv to functional loop structure in EDIII of the DENV E protein. The neutralizing Hu Sc Fv molecule warrants further development as a therapeutic biomolecule for DENV infection. Significance and Impact of the Study No approved vaccine and specific drug for dengue virus ( DENV) infection are available; thus, their developments are urgently required. The human single-chain variable antibody fragments ( Hu Sc Fv) specific to DENV envelope ( E) protein are potential to be developed as therapeutic biomolecules. Hu Sc Fv that bound specifically to recombinant full-length DENV E ( FL- E) and its domain III ( EDIII) were generated and testified for its inhibitory effect in DENV infection. EDIII-specific Hu Sc Fv inhibited DENV infection in a dose-dependent manner and has potential to be further developed as a therapeutic biomolecule for DENV infection. [ABSTRACT FROM AUTHOR]