This study reports the structural analysis of eight distinct human neutralizing antibodies (NAbs) against SARS-CoV-2, revealing their binding modes and classification into four categories. The antibodies target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Class 1 antibodies, encoded by the VH3-53 gene segment, block ACE2 and bind only to 'up' RBDs. Class 2 antibodies, also encoded by VH3-53, can bind both 'up' and 'down' RBDs and can contact adjacent RBDs. Class 3 antibodies bind outside the ACE2 site and recognize both 'up' and 'down' RBDs. Class 4 antibodies do not block ACE2 and bind only to 'up' RBDs. The study identifies structural features that determine the neutralization mechanism and potency of these antibodies. It also highlights the importance of understanding antibody-antigen interactions for developing effective therapeutic strategies. The findings provide insights into the immune response against SARS-CoV-2 and suggest potential combinations for clinical use. The study also discusses the impact of RBD substitutions on NAb binding and the potential for therapeutic strategies involving different classes of NAbs. The results contribute to the understanding of SARS-CoV-2 neutralization mechanisms and the design of antibody-based therapies.This study reports the structural analysis of eight distinct human neutralizing antibodies (NAbs) against SARS-CoV-2, revealing their binding modes and classification into four categories. The antibodies target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Class 1 antibodies, encoded by the VH3-53 gene segment, block ACE2 and bind only to 'up' RBDs. Class 2 antibodies, also encoded by VH3-53, can bind both 'up' and 'down' RBDs and can contact adjacent RBDs. Class 3 antibodies bind outside the ACE2 site and recognize both 'up' and 'down' RBDs. Class 4 antibodies do not block ACE2 and bind only to 'up' RBDs. The study identifies structural features that determine the neutralization mechanism and potency of these antibodies. It also highlights the importance of understanding antibody-antigen interactions for developing effective therapeutic strategies. The findings provide insights into the immune response against SARS-CoV-2 and suggest potential combinations for clinical use. The study also discusses the impact of RBD substitutions on NAb binding and the potential for therapeutic strategies involving different classes of NAbs. The results contribute to the understanding of SARS-CoV-2 neutralization mechanisms and the design of antibody-based therapies.