Pneumococcal disease (PD) leads to considerable morbidity, mortality, and healthcare resource utilization in children. This study estimated incidence rates (IRs) for invasive PD (IPD), all-cause pneumonia (ACP), and acute otitis media (AOM) among children ≤ 48 months old, between 2010 and 2019 in the US. This was a retrospective observational study using MarketScan® Commercial Claims and Encounters (CCAE) and Multi-State Medicaid databases (2010-2019). Date of birth was imputed using dates of live-birth claims for accurate age determination. IPD, ACP, and AOM claims in children ≤48 months old were identified using International Classification of Diseases (ICD) versions 9 and 10 diagnosis codes. Episodes were defined as one or more PD-related claims, with a gap of 90 days between two IPD or ACP claims, and 14 days between two AOM claims. IRs were defined as number of episodes per 100,000 person-years (PY) for IPD and ACP, and per 1,000 PY for AOM. Annual IRs were stratified by age (0-6, 7-12, 13-24, and 25-48 months), and reported separately for CCAE and Medicaid populations. IPD incidence in commercially and Medicaid-insured children ages 0 - 48 months, episodes per 100,000 patient-years (2010 - 2019) ACP incidence in commercially and Medicaid-insured children ages 0 - 48 months, episodes per 100,000 patient-years (2010 - 2019) AOM incidence in commercially and Medicaid-insured children ages 0 - 48 months, episodes per 1,000 patient-years (2010 - 2019) IPD, ACP, and AOM IRs disease burden remains substantial with a disproportionately high impact of the most severe disease manifestations (IPD and inpatient ACP) among infants in the first year of life, despite marked declines following the introduction of PCV13. Disease IRs were generally higher in Medicaid children, particularly at the start of the study period, but also declined more significantly over time compared to IRs in CCAE children. Salini Mohanty, DrPH, MPH, Employee of Merck & Co., Inc.: Stocks/Bonds Nicolae Done, PhD, Merck & Co., Inc.: Grant/Research Support Qing liu, PhD, Merck & Co., Inc.: Advisor/Consultant Yan Song, PhD, Merck & Co., Inc.: Grant/Research Support Katherine Gaburo, n/a, Merck & Co., Inc.: I am an employee of Analysis Group, Inc., which received consulting fees for participation in this research Travis Wang, MS, MBBS, Merck & Co., Inc.: Grant/Research Support Meghan White, PharmD, Merck: Employee|Merck: Stocks/Bonds Jessica P. Weaver, PhD, Employee of Merck & Co., Inc.: Stocks/Bonds James Signorovitch, PhD, Merck & Co., Inc.: Grant/Research Support Thomas Weiss, DrPH, MPH, Employee of Merck & Co., Inc.: Stocks/Bonds