Zika virus (ZIKV) infection in both infants and adults is associated with neurological complications including, but not limited to, microcephaly and Guillain-Barre syndrome. Antibody therapy can be effective against virus infection. We isolated ZIKV envelope domain III-specific neutralizing antibodies (nAbs) from two convalescent patients with ZIKV infection. One antibody, 2F-8, exhibited potent in vitro neutralizing activity against Asian and American strains of ZIKV. To prevent Fc gamma R-mediated antibody dependent enhancement, we prepared IgG1 with LALA variation. A single dose of 2F-8 in the context of IgG1 or IgG1-LALA prior to or post lethal ZIKV challenge conferred complete protection in mice. (C) 2021 The Authors. Published by Elsevier Inc.