Antibody-dependent enhancement (ADE) has been reported in several virus infections including dengue fever virus, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus infection. To study whether ADE is involved in COVID-19 infections, in vitro pseudotyped SARS-CoV-2 entry into Raji cells, K562 cells, and primary B cells mediated by plasma from recovered COVID-19 patients were employed as models. The enhancement of SARS-CoV-2 entry into cells was more commonly detected in plasma from severely-affected elderly patients with high titers of SARS-CoV-2 spike protein-specific antibodies. Cellular entry was mediated via the engagement of FcγRII receptor through virus-cell membrane fusion, but not by endocytosis. Peptide array scanning analyses showed that antibodies which promote SARS-CoV-2 infection targeted the variable regions of the RBD domain. To further characterize the association between the spike-specific antibody and ADE, an RBD-specific monoclonal antibody (7F3) was isolated from a recovered patient, which potently inhibited SARS-Cov-2 infection of ACE-2 expressing cells and also mediated ADE in Raji cells. Site-directed mutagenesis the spike RBD domain reduced the neutralization activity of 7F3, but did not abolish its binding to the RBD domain. Structural analysis using cryo-electron microscopy (Cryo-EM) revealed that 7F3 binds to spike proteins at a shift-angled pattern with one “up” and two “down” RBDs, resulting in partial overlapping with the receptor binding motif (RBM), while a neutralizing monoclonal antibody that lacked ADE activity binds to spike proteins with three “up” RBDs, resulting in complete overlapping with RBM. Our results revealed that ADE mediated by SARS-CoV-2 spike-specific antibodies could result from binding to the receptor in slightly different pattern from antibodies mediating neutralizations. Studies on ADE using antibodies from recovered patients via cell biology and structural biology technology could be of use for developing novel therapeutic and preventive measures for control of COVID-19 infection. ### Competing Interest Statement Patents about the monoclonal antibodies 7F3 and 4L12 in this study are pending. ### Funding Statement This work was supported by the National Natural Science Foundation of China (31771008 to JH, 31930001 to YZ and FW, 82041025 to SJ, and 31971123 to QZ), the National Major Science and Technology Projects of China (2017ZX10202102 to JH and 2018ZX10301403 to FW and LL), Hundred Talent Program of Shanghai Municipal Health Commission (2018BR08 to JH), Chinese Academy of Medical Sciences (2019PT350002 to JH), Program of Shanghai Academic/Technology Research Leader (20XD1420300 to LL), the Key R&D Program of Zhejiang Province (2020C04001), the SARS-CoV-2 Emergency Project of the Science and Technology Department of Zhejiang Province (2020C03129), the Leading Innovative and Entrepreneur Team Introduction Program of Hangzhou, and the Special Research Program of Novel Coronavirus Pneumonia of Westlake University and Tencent foundation to QZ. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted under a clinical protocol approved by the Investigational Review Board in the Shanghai Public Health Clinical Center (Study number: YJ-2020-S018-02). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Correspondence and requests for all data should be addressed to Jinghe Huang (jinghehuang@fudan.edu.cn)