OBJECTIVES: To assess the association of second-generation antipsychotics prescriptions (SGAs) with changes in body mass index (BMI) among adolescents compared to a randomly selected age and gender matched untreated comparison group. METHODS: A retrospective cohort study was conducted using an ambulatory electronic medical record database between January 2004 and July 2009. Antipsychotic naïve (no evidence of SGAs during 540 days pre index period) monotherapy adolescents 12–19 years with at least one prescription for any SGA during 395 days follow-up period were eligible. The comparison group without antipsychotic prescription was matched (3:1) to the antipsychotic group based on age, gender, and month of SGA. A maximum follow-up BMI 90 days post index date was evaluated and percentage change from baseline BMI was calculated. Multivariate linear regression was conducted to assess the percent change in follow-up BMI from baseline among antipsychotic users compared to the comparison group controlling for covariates. RESULTS: The mean age (15.35 years, SD 2.27) and gender (males, 53%) distribution among the antipsychotic group (n=793) was similar (p>0.05) to the comparison group (n=2,373). The mean percentage increase in follow-up BMI from baseline for antipsychotic group was significantly higher than the comparison group (p<0.01) except for ziprasidone (p>0.05). After adjusting for covariates, adolescents on olanzapine had the highest percentage increase in follow-up BMI from baseline (5.84%, 95% Confidence Interval [CI], 4.07–7.61) followed by aripiprazole (4.36%; 95% CI, 3.08–5.64), risperidone (3.65%; 95% CI, 2.61–4.68), and quetiapine (1.53%; 95% CI, 0.53–2.52) compared to the comparison group. Normal weight adolescents on antipsychotics had higher percentage increase in follow-up BMI from baseline compared to overweight or obese. CONCLUSIONS: Treatment with SGAs is associated with significant increase in BMI among adolescents relative to a matched comparison group. Interventions to control weight gain should be considered in adolescents treated with SGAs.