Objective To evaluate the frequency of medical imaging or estimated associated radiation exposure in children with Down syndrome. Methods This retrospective cohort study included 4,348,226 children enrolled in six U.S. integrated healthcare systems from 1996–2016, 3,095 of whom were diagnosed with Down syndrome. We calculated imaging rates per 100 person years and associated red bone marrow dose (mGy). Relative rates (RR) of imaging in children with versus without Down syndrome were estimated using overdispersed Poisson regression. Results Compared to other children, children with Down syndrome received imaging using ionizing radiation at 9.5 times (95% confidence interval[CI] = 8.2–10.9) the rate when age <1 year and 2.3 times (95% CI = 2.0–2.5) between ages 1–18 years. Imaging rates by modality in children <1 year with Down syndrome compared with other children were: computed tomography (6.6 vs. 2.0, RR = 3.1[95%CI = 1.8–5.1]), fluoroscopy (37.1 vs. 3.1, RR 11.9[95%CI 9.5–14.8]), ang