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Introduction: Individuals with intellectual and developmental disabilities are at increased risk for adverse outcomes from coronavirus disease 2019. Clusters of COVID-19 infections can be used to track SARS-CoV-2 transmission. This is particularly important in environments frequently used for individuals with intellectual and developmental disabilities, such as schools. The objective of this study was to compare the number of clusters of student and staff cases identified during three distinct periods (pre-Delta, Delta, and Omicron) of the COVID-19 pandemic., Methods: Weekly COVID-19 testing occurred from November 23, 2020 to May 27, 2022 during three phases of the COVID-19 pandemic: pre-Delta, Delta, and Omicron. Structured interviews were conducted with positive cases to determine if they contracted COVID-19 in the school environment, and interviews with school administrators responsible for contact tracing determined school-based clusters., Results: 160 cases of COVID-19 were identified and 55 cluster positives were recorded during the study period. 0 (0%) cluster positives were recorded during the pre-Delta variant wave, 3 (5%) cluster positives were recorded during the Delta variant wave, and 52 (95%) cluster positives were recorded during the Omicron variant wave. Additionally, 23 (85%) of all positives during pre-Delta, 12 (50%) of all positives during Delta, 66 (61%) of all positives during Omicron, and 36 (69%) of cluster positives during Omicron did not receive CDC-recommended dosages of the COVID-19 vaccine., Conclusion: The Omicron variant led to an increase in cluster-based transmission, and staying up to date with vaccination guidelines was crucial in limiting transmission., Clinical Trial Registration: Prior to enrollment, this study was registered at ClinicalTrials.gov on September 25, 2020 (identifier NCT04565509; titled "Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic")., (© 2023. The Author(s).)