The variant SARS-CoV-2 B.1.1.529 (Omicron) contains 15 mutations on the receptor binding domain (RBD). How Omicron would bypass RBD Neutralizing Antibodies (NAbs) requires immediate investigation. Here we have used high throughput yeast display screening1,2 determine the RBD escape mutation profiles for 247 human anti-RBD NAbs and demonstrated that the NAbs can be unattended clustered into six epitope groups (AF), which is in high agreement with knowledge-based structural classifications3-5. Notably, different single mutations of Omicron NAbs could affect different epitope groups. In particular, NAbs in group AD, whose epitope overlaps the ACE2 binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Group E (location S309)6 und F (CR3022-Site)7 NAbs, which often have broad Sarbecovirus neutralizing activity, are less affected by Omicron, but nonetheless, a subset of NAbs will escape G339D, N440K, and S371L. In addition, the Omicron pseudovirus neutralization showed that even single mutation-tolerant NAbs could escape due to multiple synergistic mutations at their epitopes. Overall, over 85% of the Omicron NAbs tested will escape. Regarding NAb drugs, the strength of neutralization of LY-CoV016 / LY-CoV555, REGN10933 / REGN10987, AZD1061 / AZD8895 and BRII-196 was greatly reduced by Omicron, while VIR-7831 and DXP-604 still function with reduced effectiveness. Taken together, the data suggest that Omicron would cause significant humoral immune evasion, while NAbs, which target the region conserved by the Sarbecovirus, remain most effective. Our results provide guidance for the development of NAb drugs and vaccines against Omicron and future variants.