The development of a universal influenza vaccine likely requires an understanding of previous exposure to influenza virus (through vaccination or infection) and how that shapes the antibody repertoire to vaccination, sometimes called original antigenic sin or antigenic imprinting. While animal models can have a much more defined exposure history, they lack a human B-cell repertoire. Transgenic mice with the complete human immunoglobulin locus enable studies of controlled infection history leading to human-like antibody evolution. Here we evaluated responses to influenza in the Intelliselect transgenic mouse (the Kymouse). We show the Kymouse is susceptible to disease following infection with either H1N1, H3N2, or B/Yamagata influenza viruses and that it induces a robust binding and neutralizing antibody response to all 3 strains of influenza virus. This study demonstrates that human B-cell repertoire mice can be used for influenza virus studies, providing a tool for further interrogation of the antibody response.