To compare weight and glucose changes of long-term second-generation antipsychotic (SGA) monotherapy versus polytherapy (switching or combining SGAs) in children and adolescents. This is a 24-month retrospective study conducted between November 2005 and June 2013. From 147 antipsychotic-naive patients selected (mean age, 12.8 years; 95% confidence interval [CI], 9.8-15.9), 116 (78.9%) received SGA monotherapy and 31 (21.1%) SGA polytherapy for up to 24 months. Height, weight, and fasting glucose (FG) were measured at baseline and 1, 3, 6, 12, and 24 months. Linear mixed-model analysis was used to compare weight, body mass index z score (BMI z score), and glucose changes between the 2 SGA treatment groups, with the repeated factor being the time relative to baseline at 1, 3, 6, 12, and 24 months. Overall, after 24 months of SGA treatment, mean weight increased significantly by 12.8 kg (95% CI, 10.4-15.0), BMI z score by 0.44 (95% CI, 0.21-0.68), and FG levels by 0.29 mmol/L (95% CI, 0.11-0.47). Incidence of overweight/obesity was 22.6%, BMI z score increase over 0.5 was 9.4%, impaired fasting glucose was 9.4%, and type 2 diabetes mellitus was 3.1%. Regarding metabolic effects, no significant difference was found between the subjects taking a single SGA and those exposed to an SGA polytherapy. Our study confirms the significant increase of metabolic complications during 24 months of SGA treatment without excluding or confirming a difference between the 2 groups of treatment (mono vs. poly).