Neuroimaging studies have indicated abnormalities in cortico-striato- thalamo-cortical circuits in obsessive-compulsive disorder patients, but results have not been consistent. Since there are significant sex differences in human brain anatomy and obsessive-compulsive symptomatology and its developmental trajectories tend to be distinct in males and females, we investigated whether sex is a potential source of heterogeneity in neuroimaging studies on obsessive-compulsive symptoms. We selected male and female twin pairs who were concordant for scoring either high or low for obsessive-compulsive symptoms and a group of discordant pairs where one twin scored high and the co-twin scored low. The design included 24 opposite-sex twin pairs. Magnetic resonance imaging scans of 31 males scoring high for obsessive-compulsive symptoms, 41 low-scoring males, 58 high-scoring females, and 73 low-scoring females were analyzed and the interaction of obsessive-compulsive symptoms by sex on gray matter volume was assessed using voxel-based morphometry. An obsessive-compulsive symptom by sex interaction was observed for the left middle temporal gyrus, the right middle temporal gyrus, and the right precuneus. These interactions acted to reduce or hide a main effect in our study and illustrate the importance of taking sex into account when investigating the neurobiology of obsessive-compulsive symptoms. © The Authors 2013.