CONTEXT Cardiometabolic effects of second-generation antipsychotic medications are concerning but have not been sufficiently studied in pediatric and adolescent patients naive to antipsychotic medication. OBJECTIVE To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure. DESIGN, SETTING, AND PATIENTS Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients who completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group. INTERVENTION Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks. MAIN OUTCOME MEASURES Weight gain and changes in lipid and metabolic parameters. RESULTS After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval CI, 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, −1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL 95% CI, 6.9 to 24.3 mg/dL P < .001 and 9.1 mg/dL 95% CI, 0.4 to 17.7 mg/dL P = .046), triglycerides (24.3 mg/dL 95% CI, 9.8 to 38.9 mg/dL P = .002 and 37.0 mg/dL 95% CI, 10.1 to 63.8 mg/dL P = .01), non–high-density lipoprotein (HDL) cholesterol (16.8 mg/dL 95% CI, 9.3 to 24.3 mg/dL P < .001 and 9.9 mg/dL 95% CI, 1.4 to 18.4 mg/dL P = .03), and ratio of triglycerides to HDL cholesterol (0.6 95% CI, 0.2 to 0.9 P = .002 and (1.2 95% CI, 0.4 to 2.0 P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL 95% CI, 0.5 to 19.0 mg/dL; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group. CONCLUSIONS First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.