The use of broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals in the development of an effective AIDS vaccine has been limited by potency and breadth of protection. Now, Xu et al. report the generation of multi-specific antibodies derived from bnAbs with specificities for three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region and the V1V2 glycan site. In contrast to single bnAbs, these trispecific antibodies conferred complete immunity against a mixture of two different simian–human immunodeficiency viruses (SHIVs) in non-human primates.