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Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 infection in children and adolescents primarily causes mild or asymptomatic coronavirus disease 2019 (COVID-19), and severe illness is mainly associated with comorbidities. However, the worldwide prevalence of COVID-19 in this population is only 1%–2%. In Mexico, the prevalence of COVID-19 in children has increased to 10%. As serology-based studies are scarce, we analyzed the clinical features and serological response (SARS-CoV-2 structural proteins) of children and adolescents who visited the Hospital Infantil de México Federico Gómez (October 2020–March 2021). The majority were 9-year-old children without comorbidities who were treated as outpatients and had mild-to-moderate illness. Children aged 6–10 years and adolescents aged 11–15 years had the maximum number of symptoms, including those with obesity. Nevertheless, children with comorbidities such as immunosuppression, leukemia, and obesity exhibited the lowest antibody response, whereas those aged 1–5 years with heart disease had the highest levels of antibodies. The SARS-CoV-2 spike receptor-binding domain-localized peptides and M and E proteins had the best antibody response. In conclusion, Mexican children and adolescents with COVID-19 represent a heterogeneous population, and comorbidities play an important role in the antibody response against SARS-CoV-2 infection.