Second-generation antipsychotic (SGA) medications are associated with cardiometabolic risk factors such as obesity and elevated blood pressure (BP) in some individuals. The goal of this study is to determine whether the Val158Met variant (rs4680) in the catechol-O-methyltransferase (COMT) gene, associated with BP in adults, is associated with elevated BP in SGA-treated children. A cross-sectional population of SGA-treated (n = 134) and SGA-naive (n = 168) children, ≤ 18 years of age, were genotyped and assessed for markers of cardiometabolic health. An interaction was found between SGA treatment and COMT genotype for BP. After adjusting for covariates, SGA-treated children with the Met allele had higher systolic and diastolic BP (P = 0.014 and P = 0.034, respectively), and higher fasting glucose concentrations (P = 0.030) compared with children with the Val/Val genotype. This was not observed in SGA-naive children. The Met allele of the COMT Val158Met variant may identify SGA-treated children at risk for elevated BP and fasting blood glucose concentrations.