Dysregulated immune cell responses have been linked to the severity of coronavirus disease 2019 (COVID-19), but the specific viral factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were currently unknown . Herein, we reveal that the Ig-like fold ectodomain of the viral protein SARS-CoV-2 ORF7a interacts with high efficiency to CD14+ monocytes in human peripheral blood, compared to pathogenic protein SARS-CoV ORF7a . The crystal structure of SARS-CoV-2 ORF7a at 2.2 Å resolution reveals three remarkable changes on the amphipathic side of the four-stranded β-sheet, implying a potential functional interface of the viral protein . Importantly, SARS-CoV-2 ORF7a coincubation with CD14+ monocytes ex vivo triggered a decrease in HLA-DR/DP/DQ expression levels and upregulated significant production of proinflammatory cytokines, including IL-6, IL-1β, IL-8, and TNF-α . Our work demonstrates that SARS-CoV-2 ORF7a is an immunomodulating factor for immune cell binding and triggers dramatic inflammatory responses, providing promising therapeutic drug targets for pandemic COVID-19.