A human monoclonal antibody, 10E8, specific for the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes approximately 98% of tested HIV-1 viruses. This antibody is highly effective and does not bind phospholipids or autoantigens, making it a promising candidate for HIV-1 vaccines. The structure of 10E8 in complex with the MPER reveals a conserved site of vulnerability, consisting of highly conserved gp41 hydrophobic residues and a critical Arg/Lys residue near the transmembrane region. Analysis of resistant HIV-1 variants confirms the importance of these residues for neutralization. 10E8 is one of the most broadly and potently neutralizing antibodies, with a unique mode of recognition of a structurally conserved site within the MPER. It is not autoreactive and has a high affinity for the MPER, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 Env. The prevalence of 10E8-like antibodies in HIV-1-infected donors is higher than previously observed, indicating that such antibodies may not be rare. 10E8 does not bind to anionic phospholipids or autoantigens, distinguishing it from other MPER-specific antibodies. The antibody has modest access to the MPER epitope on the cell surface, and its structure reveals a unique epitope that overlaps with known 4E10 and Z13e1 epitopes but differs in critical binding interactions. The structure of 10E8 in complex with the MPER highlights a conserved site of vulnerability in gp41, which is an important target for HIV-1 neutralization. The study provides insights into the mechanisms of broad and potent HIV-1 neutralization and suggests that targeting the MPER could be a key strategy for HIV-1 vaccine development.A human monoclonal antibody, 10E8, specific for the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes approximately 98% of tested HIV-1 viruses. This antibody is highly effective and does not bind phospholipids or autoantigens, making it a promising candidate for HIV-1 vaccines. The structure of 10E8 in complex with the MPER reveals a conserved site of vulnerability, consisting of highly conserved gp41 hydrophobic residues and a critical Arg/Lys residue near the transmembrane region. Analysis of resistant HIV-1 variants confirms the importance of these residues for neutralization. 10E8 is one of the most broadly and potently neutralizing antibodies, with a unique mode of recognition of a structurally conserved site within the MPER. It is not autoreactive and has a high affinity for the MPER, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 Env. The prevalence of 10E8-like antibodies in HIV-1-infected donors is higher than previously observed, indicating that such antibodies may not be rare. 10E8 does not bind to anionic phospholipids or autoantigens, distinguishing it from other MPER-specific antibodies. The antibody has modest access to the MPER epitope on the cell surface, and its structure reveals a unique epitope that overlaps with known 4E10 and Z13e1 epitopes but differs in critical binding interactions. The structure of 10E8 in complex with the MPER highlights a conserved site of vulnerability in gp41, which is an important target for HIV-1 neutralization. The study provides insights into the mechanisms of broad and potent HIV-1 neutralization and suggests that targeting the MPER could be a key strategy for HIV-1 vaccine development.