The serotonin 2Areceptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations ofAfrican andEuropean descent;rs6311, which affectsmRNAexpression, andrs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for theseSNPsin cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158ASDtrios (simplex and multiplex), observing significant under‐transmission of the minor “A” allele of rs6311 to offspring withASD(permutedP = 0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals,rs6311/A decreases expression ofHTR2AmRNAwith an extended 5′ untranslated region (UTR) in the frontopolar cortex in brain samples from 54ASDpatients and controls. Interpreting the clinical results in the context of ourmRNAexpression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5′UTR mRNAisoform. The current study corroborates earlier associations betweenrs6311 andASDin a family study, supporting the hypothesis thatrs6311 plays a modulatory role inASDrisk.Autism Res2014, 7: 459–467.© 2014 International Society for Autism Research, Wiley Periodicals, Inc.