We describe here the isolation of three mAbs from a large naive human phage-displayed Fab library. One, designated as m252, is against the F1-antigen and the other two (m253, m254) are against the V-antigen. When used alone, m252 displayed good protective effects, whereas m253 and m254 did not. However, a clear synergistic effect was found when they were used together. Maximum protection by m252 alone could be achieved by altering the antibody administration schedule. This is the first report describing the isolation of fully human anti-plague mAbs that show efficacy in a mouse model of plague. These antibodies represent a significant breakthrough toward possible adjunctive therapeutic treatment of Y. pestis infection in humans.