© Copyright 2016, Mary Ann Liebert, Inc. 2016. Objective: Irritability (aggression, self-injury, and severe tantrums) associated with autism spectrum disorder (ASD) is often treated with second-generation antipsychotics (SGAs), which are well known for their associated risk of weight gain in youth. Recent reports suggest that youth with ASD treated with SGAs may suffer more pronounced weight gain than typically developing children. In this study, we present a comprehensive comparison of weight gain effects of five SGAs in a clinical population of youth with ASD. Methods: We completed a subanalysis of demographic and treatment data describing 202 youth with ASD treated at two large, subspecialty psychiatry clinics. Included subjects were between 2 and 20 years of age and were treated with one of five SGAs (risperidone, aripiprazole, olanzapine, quetiapine, or ziprasidone) for up to 4 years. We calculated change in each participant's body-mass index (BMI) z-score during the treatment period using a linear model where the dependent variable was change in BMI z-score and the independent variables were SGA used and duration of treatment. First, these models were run for each drug separately, then the SGA groups were run together to estimate differences between groups. We also adjusted these models for weight gain-attenuating concomitant medications. Results: Treatment with risperidone, aripiprazole, and olanzapine resulted in statistically significant increase in BMI z-score (p = 0.03, 0.05, and <0.01 respectively). Ziprasidone and quetiapine were not associated with an increase in BMI z-score in this analysis (p = 0.47 and p = 0.11). Subjects treated with olanzapine showed a statistically significant greater increase in BMI z-score when compared with the other SGAs (all p-values <0.05). These results did not change when adjusted for multiple testing or weight gain-attenuating medication as covariate. Conclusion: Clinicians treating youth with ASD may be able to use this information to balance the risks and benefits of SGA treatment when managing ASD-associated irritability.