ABSTRACT While an increasing number of behavioral findings have provided gene-culture coevolution accounts of human development, whether and how the brain mediates gene-culture associations remain unresolved. Based on the Culture-Behavior-Brain-Loop Model and the recent finding of associations between the oxytocin receptor gene (OXTR, rs53576) and a cultural trait (i.e., interdependence) across populations, we tested the hypothesis that resting-state brain network properties mediate the relationship between OXTR rs53576 and interdependence. G and A allele carriers of OXTR rs53576 were scanned during a resting state using functional magnetic resonance imaging (fMRI) and completed questionnaires to estimate their interdependence cultural values. We identified significant genotype effects on the local network metrics of the right hippocampus and its functional connectivity with the medial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, basal ganglia and thalamus. The local network metrics of the right hippocampus and its functional connectivity with the basal ganglia and thalamus were correlated with interdependence. Moreover, both the degree of the right hippocampus and its functional connectivity with the basal ganglia and thalamus mediated the relationship between OXTR and interdependence. Our results provide brain imaging evidence for a key function of the brain in mediating the relationship between genes and culture.