Seroprevalence studies play an important role in estimating the number of children infected with SARS-CoV-2. We report SARS-CoV-2 seroprevalence in children seeking medical care for any reason at a free-standing pediatric hospital in Seattle, WA over a 2.5-year period and four distinct pandemic waves. We randomly selected residual serum samples from children and young adults seeking medical care as inpatients and outpatients at Seattle Children's Hospital between June 2020 and December 2022 to test for the presence of anti-nucleocapsid (N) antibodies. Samples were categorized into four distinct pandemic waves based on Washington State epidemiology: Wave 1 (June 2020-October 2020), Wave 2 (November 2020-June 2021), Wave 3 (July 2021-November 2021), and Wave 4 (December 2021-December 2022). Patient characteristics and COVID-19 vaccine status were obtained, and zip codes were used to ascertain the Social Vulnerability Index (SVI). Multivariable Poisson regression models with robust variance estimates were used to examine the relationship between patient characteristics and anti-N-positivity for each wave. Among 8,040 samples from 7,102 patients included in the analyses, seroprevalence rose from 2.4% (95% CI, 2.0%-3.1%) in Wave 1 to 25.5% (95% CI 23.3%-27.8%) in Wave 4 (following the Omicron surge). High SVI, Hispanic ethnicity, or use of government insurance was associated with increased anti-N positivity in most waves. We observed a steady increase in anti-N seroprevalence followed by a sharp increase after the Omicron surge in early 2022. Our data demonstrate the burden of COVID-19 on specific groups with health disparities within our region throughout the pandemic.IMPORTANCEOur results highlight the importance of seropositivity studies as essential tools to provide information on the incidence and prevalence of SARS-CoV-2 seropositivity. Our results also reinforce other reports demonstrating the inequitable burden of COVID-19 on groups with health disparities and that this inequitable burden continued to persist throughout the pandemic, even in a region with high adherence to COVID-19 mitigation efforts. It also highlights SVI's value in identifying communities that must be part of pandemic research, and public health and vaccination strategies.