Objectives. To evaluate community-wide prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using stratified simple random sampling. Methods. We obtained data for the prevalence of SARS-CoV-2 in Jefferson County, Kentucky, from adult random (n = 7296) and volunteer (n = 7919) sampling over 8 waves from June 2020 through August 2021. We compared results with administratively reported rates of COVID-19. Results. Randomized and volunteer samples produced equivalent prevalence estimates (P < .001), which exceeded the administratively reported rates of prevalence. Differences between them decreased as time passed, likely because of seroprevalence temporal detection limitations. Conclusions. Structured targeted sampling for seropositivity against SARS-CoV-2, randomized or voluntary, provided better estimates of prevalence than administrative estimates based on incident disease. A low response rate to stratified simple random sampling may produce quantified disease prevalence estimates similar to a volunteer sample. Public Health Implications. Randomized targeted and invited sampling approaches provided better estimates of disease prevalence than administratively reported data. Cost and time permitting, targeted sampling is a superior modality for estimating community-wide prevalence of infectious disease, especially among Black individuals and those living in disadvantaged neighborhoods. (Am J Public Health. 2023;113(7):768-777. https://doi.org/10.2105/AJPH.2023.307303).