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Summary The major mechanism of antibody-mediated neutralization of the Middle East respiratory syndrome coronavirus (MERS-CoV) involves competition with the cellular receptor dipeptidyl peptidase 4 (DPP4) for binding to the receptor-binding domain (RBD) of the spike (S) glycoprotein. Here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody MERS-4. Structurally, MERS-4 approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the β5-β6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4. The key residues for binding are identified through site-directed mutagenesis. Structural modeling revealed that MERS-4 binds to RBD only in the “up” position in the S trimer. Furthermore, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection., Graphical Abstract, Highlights • MERS-4 binds RBD from the outside of the RBD–DPP4 binding interface • MERS-4 favors binding to the RBD in the “up” position in the S trimer • MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4 • MERS-4 is a valuable addition to the combined use of MERS-CoV antibodies, Zhang et al. report the structural and functional analysis of the potent MERS-CoV neutralizing antibody MERS-4. MERS-4 recognizes a unique epitope and indirectly disrupts interaction between the receptor binding domain and the receptor DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection.