Weight gain is an important adverse effect of risperidone, but predictors of significant weight gain have yet to be identified in pediatric patients. Here, we investigated differences between age- and gender-normed body mass index-standardized z scores at baseline and after 8 weeks of open-label, flexible-dose risperidone treatment (mean dose: 1.70 mg/day) in 32 youths with pervasive developmental disorder (mean age = 8.74, range = 5-16 years) in relation to -759C/T 5-hydroxytryptamine 2C receptor (HTR2C) promoter and rs1414334 HTR2C intragenic C/G alleles, along with gender, age, and risperidone dose, using repeated measures analyses of variance. Carriers of the HTR2C promoter T allele gained an average of 0.043 ± 0.017 body mass index-standardized z scores (1.84 ± 1.51 kg) versus 0.64 ± 0.35 z (3.23 ± 1.47 kg) for non-T-allele carriers (p < 0.001). Presence of the rs1414334 C allele played no significant role. Further, weight gain appeared to be associated with younger age and higher doses of risperidone. The current preliminary findings suggest that the variant T allele of the -759C/T HTR2C promoter polymorphism is protective against risperidone-induced weight gain. Younger children and those treated with higher doses of risperidone may be at higher risk for weight gain.