The intelligence quotient (IQ) is typically associated with the architecture of gray and white matter in specific brain regions, and this association appears to be genetically based. However, specific sources of genetic variation for the association have not been studied extensively. Using diffusion tensor imaging in 15 mental retardation patients and 80 healthy volunteers, we studied the association between white matter architecture and IQ and also investigated the effects of COMT val158met on this association. The results showed that fractional anisotropy (FA) values in the prefrontal lobe and the hippocampus formation were associated with IQ and that val158met may affect this association. Subjects who were val homozygous showed steeper slopes for regression of the FA value on IQ than met carriers. Our findings suggest that COMT val158met may contribute to intelligence by affecting the association between IQ and the white matter architecture in the prefrontal lobe and the hippocampal formation. © 2008 Wiley-Liss, Inc.