Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections in endemic regions. Vaccines and therapeutics in development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts are limited by a poor understanding of antibody responses elicited by infection. Here, we analyze S-directed antibody responses in plasma collected from MERS-CoV-infected individuals. We observe that binding and neutralizing antibodies peak 1-6 weeks after symptom onset/hospitalization, persist for at least 6 months, and neutralize human and camel MERS-CoV strains. We show that the MERS-CoV S(1) subunit is immunodominant and that antibodies targeting S(1), particularly the receptor-binding domain (RBD), account for most plasma neutralizing activity. Antigenic site mapping reveals that plasma antibodies frequently target RBD epitopes, whereas targeting of S(2) subunit epitopes is rare. Our data reveal the humoral immune responses elicited by MERS-CoV infection, which will guide vaccine and therapeutic design.