BACKGROUND: Autism is a highly varied and heritable neurodevelopmental condition, and common variants explain approximately 50% of the genetic variance of autism. One of the genes implicated in autism is the oxytocin receptor (OXTR). The current study combined genetic and brain imaging (fMRI) data to examine the moderating effect of genotype on the association between diagnosis and brain activity in response to a test of cognitive empathy. METHODS: Participants were adolescents (mean age = 14.7 ± 1.7) who were genotyped for single nucleotide polymorphisms (SNPs) within the OXTR and underwent functional brain imaging while completing the adolescent version of the 'Reading the Mind in the Eyes' Test (Eyes Test). RESULTS: Two (rs2254298, rs53576) of the five OXTR SNPs examined were significantly associated with brain activity during the Eyes Test, and three of the SNPs (rs2254298, rs53576, rs2268491) interacted with diagnostic status to predict brain activity. All of the effects localized to the right supramarginal gyrus (rSMG) and an overlap analysis revealed a large overlap of the effects. An exploratory analysis showed that activity within an anatomically defined rSMG and genotype can predict diagnostic status with reasonable accuracy. CONCLUSIONS: This is one of the first studies to investigate OXTR and brain function in autism. The findings suggest a neurogenetic mechanism by which OXTR-dependent activity within the rSMG is related to the aetiology of autism.