OBJECTIVES: To assess the prevalence of overweight or obesity among children with medical complexity (CMC), compared with children without medical complexity, and explore potentially modifiable mechanisms. METHODS: This study involved a retrospective cohort of 41 905 children ages 2 to 18 seen in 2019 at a single academic medical center. The primary outcome was overweight or obesity, defined as a body mass index of >= 85% for age and sex. CMC was defined as $1 serious chronic condition in >= 1 system. Obesogenic conditions and medications were defined as those typically associated with excess weight gain. Multivariable logistic regression was used to adjust for common confounders. RESULTS: Of the children in the cohort, 29.5% were CMC. Overweight or obesity prevalence was higher among CMC than non-CMC (31.9% vs 18.4%, P <=.001, adjusted odds ratio [aOR] 1.27, 95% confidence interval [CI] 1.20-1.35). Among CMC, the risk for overweight or obesity was higher among children with metabolic conditions (aOR 2.09, 95% CI 1.88-2.32), gastrointestinal conditions (aOR 1.23 95% CI 1.06-1.41), malignancies (aOR 1.21 95% CI 1.07-1.38), and Spanish-speaking parents (aOR 1.47 95% CI 1.30-1.67). Among overweight or obese CMC, 91.6% had no obesogenic conditions, and only 8.5% had been seen by a registered dietitian in the previous year. CONCLUSIONS: CMC are significantly more likely to be overweight or obese when compared with children without medical complexity. Although many CMC cases of overweight appear to be preventable, further research is necessary to determine if and how to prevent comorbid obesity among CMC.