Human noroviruses are responsible for approximately 200,000 deaths worldwide each year. In 2012, the GII.4 Sydney strain emerged and became the major circulating norovirus strain associated with human disease. Our understanding of the human norovirus-specific antibody response is limited because few human monoclonal antibodies (mAbs) to noroviruses have been described and there are no functional assays to measure virus neutralization. We studied the antibody-mediated response to the GII.4 strain by isolating mAbs to GII.4 from infected patients and developing virus neutralization assays.