Following a primary DENV infection, humans develop antibodies that cross-react with all 4 serotypes, but mainly neutralize the homologous serotype responsible for the infection (Reviewed in [3] ). Studies with human immune sera and, more recently, human monoclonal antibodies have demonstrated that the dominant antibody response is cross-reactive and weakly neutralizing [25] [26] [27] [28] [29] [30] . Multiple viral antigens including E protein, premembrane (prM/M) protein and non-structural protein 1 (NSP1) are recognized by the human humoral response [25] [26] [27] [28] [29] [30] . Nonetheless, few studies have defined the actual epitopes of DENV recognized by type-specific and cross-reactive human antibodies at the structural level and compared this to the epitopes defined using mouse antibodies. The target(s) of dengue type-specific, strongly neutralizing human antibodies remain unknown. The goal of this study was to study two subjects in-depth to define the major antigens and epitopes recognized by antibodies that develop following primary human DENV infection. Defining the human B-cell epitopes on DENV is a key step towards understanding how antibodies can both enhance and inhibit the severity of DENV infections.