Previous positron emission tomography (PET) studies of patients with obsessive-compulsive disorder (OCD) have found elevated glucose metabolic rates in the orbitofrontal cortex (OFC) and caudate nuclei that normalize with response to treatment. Furthermore, OCD symptom provocation differentially activates specific subregions of the OFC, which have distinct patterns of connectivity and serve different functions. Therefore, we sought to determine the role of specific subregions of the OFC and associated subcortical structures in mediating OCD symptoms, by determining how glucose metabolism in these structures changed with paroxetine treatment of OCD patients. We also sought to determine whether pretreatment OFC metabolism would predict response to paroxetine, as it has for other OCD treatments. Twenty subjects with OCD received [18F]-fluorodeoxyglucose (FDG)-PET scans before and after 8 to 12 weeks of treatment with paroxetine, 40 mg/day. In patients who responded to paroxetine, glucose metabolism decreased significantly in right anterolateral OFC and right caudate nucleus. Lower pretreatment metabolism in both left and right OFC predicted greater improvement in OCD severity with treatment. These results add to evidence indicating that orbitofrontal-subcortical circuit function mediates the symptomatic expression of OCD. Specific subregions of the OFC may be differentially involved in the pathophysiology of OCD and/or its response to pharmacotherapy.