After exposure, human rabies is preventable by prompt application of post-exposure prophylaxis. Historically, the total number of rabies vaccine doses administered during human prophylaxis has decreased, as modern biologics have improved and scientific knowledge has grown. A review of the literature on rabies virus pathogenesis, experimental animal studies, clinical trials, epidemiological surveillance, and economic analyses was conducted to determine the potential utility of reducing the current 5-dose intramuscular series of human rabies vaccine administered in the United States. Based upon the available evidence, a reduced schedule of cell-culture rabies vaccine, administered on days 0, 3, 7, and 14, given in conjunction with rabies immune globulin, was supported and recommended by the United States Advisory Committee on Immunization Practices.