BACKGROUND: The rates of mental health diagnoses in children have increased. Children in poverty have the highest rates. The use of psychotropic medication for children has been increasing, which is concerning because of the unknown long-term effects and the increased burden on the health care system. The state of Kentucky ranks among the highest in the United States for children with mental health problems, children living in poverty, and children receiving psychotropic medication. OBJECTIVE: To examine recent trends and determinants of interclass psychotropic polypharmacy (PP) use for children and youth receiving Medicaid to inform intervention development. METHODS: A retrospective cohort study was conducted using 2012-2015 Kentucky Medicaid claims for children aged 0-17 years, with continuous enrollment for ≥ 90 days with at least 1 behavioral health diagnosis (N = 237,393). Interclass PP was defined as the presence of at least 2 psychotropic medication prescription fills for at least 2 different classes of medication that, if taken as directed, would be used concurrently for at least 90 consecutive days (allowing for a single 15-day lag). The outcome variables were the presence of any interclass PP and the number of months a child received interclass PP. We conducted a descriptive analysis and developed 2 separate generalized linear regression models to test for associations between individual characteristics of children treated with psychotropic medication for ≥ 90 days (n = 75,639) and each outcome of interest. RESULTS: For the sample of children with at least 90 days of psychotropic medication treatment, 38% had at least 3 covered months of PP over the 4 years studied. Children in foster care received alpha agonists (116 vs. 69 per 1,000 children) or antidepressants (225 vs. 176 per 1,000) at a higher rate than other children receiving Medicaid but received stimulants at a lower rate (403 vs. 638 per 1,000). The primary 2-drug class combinations were stimulants with either alpha agonists or antidepressants. Children in foster care (OR = 1.7, 95% CI = 1.58, 1.84, P < 0.001), with a bipolar disorder (OR = 2.24, 95% CI = 2.10, 2.38, P < 0.001), mood disorder not otherwise specified (OR = 1.11, 95% CI = 1.04, 1.17, P < 0.001), or autism spectrum disorders (OR = 1.17, 95% CI = 1.08, 1.26, P < 0.001) had increased the odds of ever receiving PP. Black children had lower odds (OR = 0.72, 95% CI = 0.67, 0.77, P < 0.001) of ever receiving PP. Children aged 6-11 years (beta = 3.08, 95% CI = 2.87, 3.29) and 12-17 years (beta = 1.61, 95% CI = 1.38, 1.83) had more covered months with PP compared with those aged 0-5 years. Black children had fewer covered months of PP compared with white children (beta = -1.36, 95% CI = -1.61, -1.11]. Children in foster care (beta = 1.83, 95% CI = 1.53, 2.13) had more covered months with PP. Children residing in nonurban areas had fewer months with PP (beta = -0.4, 95% CI = -0.54, -0.26) compared with those residing in urban areas, as did those children with depression (beta = -3.32, 95% CI = -3.55, -3.1), impulse control disorder (beta = -2.07, 95% CI = -2.28, -1.85), and conduct disorder (beta = -1.34, 95% CI = -1.64, -1.05). Children with bipolar disorder (beta = 3.62, 95% CI = 3.38, 3.86) and autism (beta = 2.04, 95% CI = 1.75, 2.33) had more covered months with PP. As comorbidity increased, the duration of PP treatment increased (beta = 2.49, 95% CI = 2.36, 2.62). CONCLUSIONS: The rates of PP are concerning, especially for children in foster care and children aged 6-11 years. Efforts to safeguard medication use are needed, as well as future exploration of racial differences in PP. DISCLOSURES: This project was supported by the Kentucky Cabinet for Health and Family Services, Department for Medicaid; Norton Healthcare; and the School of Medicine, Department of Pediatrics; School of Public Health and Information Sciences; and Kent School of Social Work at the University of Louisville. Kentucky Medicaid approved the use of the data and granted permission to publish but played no role in the interpretation of data. Lui is employed by Kentucky Medicaid. The other authors report no potential conflicts of interest. An earlier version of this study was presented at the Pediatric Academic Societies' Annual Meeting in Baltimore, MD, on April 30-May 3, 2016. A poster presentation was given at the Society for Developmental and Behavioral Pediatrics in Cleveland, OH, on October 14-16, 2017.