question: It is unknown whether antibody-mediated enhancement (ADE) contributes to the pathogenesis of COVID-19, and the conditions for ADE needs to be elucidated. We demonstrated that without inducing an ACE2-independent ADE on Raji cells, the neutralizing antibody CB6, a mouse anti-S1 serum and convalescent plasma induced ADE on cells expressing FcγRIIA/CD32A and low levels of endogenous ACE2. ADE occurred at sub-neutralizing antibody concentrations, indicating that unneutralized S protein was required for ADE. The enhanced infectivity of 614G variant was higher than that of 614D wildtype in the presence of antibodies, further suggesting that ADE may be influenced by virus strains with different ACE2 binding affinity. Finally, knockdown of ACE2 or treatment with a fusion-inhibition peptide EK1C4 significantly reduced ADE. In conclusion, we identified an ADE mechanism mediated by neutralizing antibodies against SARS-CoV-2. ACE2 may act as a secondary receptor required for the antibody- and FcγR-mediated enhanced entry of SARS-CoV-2.