SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoproteins of SARS-CoV-2 mediate viral entry and are the main targets for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic, and public health interventions. Here, we perform a cross-sectional study on 106 SARS-CoV-2-infected individuals to evaluate humoral responses against SARS-CoV-2 Spike. Most infected individuals elicit anti-Spike antibodies within 2 weeks of the onset of symptoms. The levels of receptor binding domain (RBD)-specific immunoglobulin G (IgG) persist over time, and the levels of anti-RBD IgM decrease after symptom resolution. Although most individuals develop neutralizing antibodies within 2 weeks of infection, the level of neutralizing activity is significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection. Display omitted Antibodies against SARS-CoV-2 Spike correlate with COVID-19 severityRBD-specific IgM and IgA decline more rapidly than IgGSARS-CoV-2 neutralizing antibodies are elicited within 2 weeks of infectionNeutralizing antibodies decline significantly after resolution of the infection Prévost et al. report a cross-sectional study on a cohort of 106 COVID-19 patients and show that most infected individuals are able to elicit a sustained antibody response over time. However, plasma neutralizing capacity wanes after infection resolution, but its implication on protection from re-infection remains unknown.