Dengue is a mosquito borne viral disease of humans, and animal models that recapitulate human immune responses and/or dengue pathogenesis are needed to understand the pathogenesis of the disease. We recently described an animal model for dengue virus (DENV) infection using humanized NOD-scid IL2rgamma(null) mice (NSG) engrafted with cord blood hematopoietic stem cells (HSC). We sought to further improve this model by co-transplantation of human fetal thymus and liver tissues into NSG (BLT-NSG) mice. Enhanced DENV-specific antibody titers were found in the sera of BLT-NSG mice compared to human cord blood HSC-engrafted NSG mice. Furthermore, B cells generated during the acute phase and in memory from splenocytes of immunized BLT-NSG mice secreted DENV-specific IgM antibodies with neutralizing activity. Human T cells in engrafted BLT-NSG mice secreted IFN-gamma in response to overlapping DENV peptide pools and HLA-A2 restricted peptides. BLT-NSG mice will provide a much-needed platform to assess human immune responses to DENV vaccines and the effects of prior immunity on subsequent DENV infections. (c) 2012 The Authors. Immunology (c) 2012 Blackwell Publishing Ltd, Immunology.