The SARS-CoV-2 Omicron variant contains 15 mutations in the receptor-binding domain (RBD), which significantly reduce the neutralizing activity of many human antibodies. A study using high-throughput yeast display screening identified that 247 human anti-RBD neutralizing antibodies can be classified into six epitope groups (A–F) based on their escape profiles. These groups align with structural classifications of antibodies targeting the RBD. Omicron mutations, such as K417N, G446S, E484A, and Q493R, largely escape antibodies in groups A–D, which overlap with the ACE2-binding motif. Antibodies in groups E and F, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but some are still escaped by mutations like G339D, N440K, and S371L. Additionally, multiple synergistic mutations on their epitopes can also lead to escape. Over 85% of the tested neutralizing antibodies are escaped by Omicron. Neutralizing antibodies targeting the conserved regions of sarbecoviruses remain effective against Omicron. The study also evaluated the neutralizing potency of several neutralizing-antibody-based drugs, finding that LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895, and BRII-196 were significantly reduced in potency against Omicron, while VIR-7831 and DXP-604 retained reduced efficacy. The results suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the conserved region of sarbecoviruses will remain most effective. The study highlights the importance of developing antibody-based drugs and vaccines against Omicron and future variants. The Omicron variant was first reported to the WHO on 24 November 2021 and was classified as a variant of concern on 26 November 2021. It contains a large number of mutations, including more than 30 in the spike protein. The RBD contains 15 of these mutations, which are critical for immune evasion and infectivity. The study provides insights into the mechanisms of immune escape by Omicron and the effectiveness of neutralizing antibodies against it.The SARS-CoV-2 Omicron variant contains 15 mutations in the receptor-binding domain (RBD), which significantly reduce the neutralizing activity of many human antibodies. A study using high-throughput yeast display screening identified that 247 human anti-RBD neutralizing antibodies can be classified into six epitope groups (A–F) based on their escape profiles. These groups align with structural classifications of antibodies targeting the RBD. Omicron mutations, such as K417N, G446S, E484A, and Q493R, largely escape antibodies in groups A–D, which overlap with the ACE2-binding motif. Antibodies in groups E and F, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but some are still escaped by mutations like G339D, N440K, and S371L. Additionally, multiple synergistic mutations on their epitopes can also lead to escape. Over 85% of the tested neutralizing antibodies are escaped by Omicron. Neutralizing antibodies targeting the conserved regions of sarbecoviruses remain effective against Omicron. The study also evaluated the neutralizing potency of several neutralizing-antibody-based drugs, finding that LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895, and BRII-196 were significantly reduced in potency against Omicron, while VIR-7831 and DXP-604 retained reduced efficacy. The results suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the conserved region of sarbecoviruses will remain most effective. The study highlights the importance of developing antibody-based drugs and vaccines against Omicron and future variants. The Omicron variant was first reported to the WHO on 24 November 2021 and was classified as a variant of concern on 26 November 2021. It contains a large number of mutations, including more than 30 in the spike protein. The RBD contains 15 of these mutations, which are critical for immune evasion and infectivity. The study provides insights into the mechanisms of immune escape by Omicron and the effectiveness of neutralizing antibodies against it.