Background: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients point to deficits in cortico-striato-thalamo-cortical circuits that might include changes in white matter. The contribution of environmental and genetic factors to the various OCD-related changes in brain structures remains to be established. Methods: White matter structures were analyzed in 140 subjects with both diffusion tensor imaging and voxel-based morphometry. We studied 20 monozygotic twin pairs discordant for obsessive-compulsive symptoms (OCS) to detect the effects of environmental risk factors for obsessive-compulsive (OC) symptomatology. Furthermore, we compared 28 monozygotic twin pairs concordant for low OCS scores with 23 twin pairs concordant for high OCS scores to detect the effects of genetic risk factors for OC symptomatology. Results: Discordant pair analysis showed that the environmental risk was associated with an increase in dorsolateral-prefrontal white matter. Analysis of concordant pairs showed that the genetic risk was associated with a decrease in inferior frontal white matter. Various white matter tracts showed opposite effects of environmental and genetic risk factors (e.g., right medial frontal, left parietal, and right middle temporal), illustrating the need for designs that separate these classes of risk factors. Conclusions: Different white matter regions were affected by environmental and genetic risk factors for OC symptomatology, but both classes of risk factors might, in aggregate, create an imbalance between the indirect loop of the cortico-striato-thalamo-cortical network (to the dorsolateral-prefrontal region)important for inhibition and switching between behaviorsand the direct loop (involving the inferior frontal region) that contributes to the initiation and continuation of behaviors. © 2011 Society of Biological Psychiatry.